Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Women With Severe Aortic Stenosis: The RHEIA Trial

Abstract

Background

In the RHEIA (Randomized Research in Women All Comers With Aortic Stenosis) trial, the incidence of the primary end point of death, stroke, or rehospitalization at 1 year was lower with transcatheter aortic valve implantation (TAVI) than with surgical aortic valve replacement. The objective of this substudy was to compare echocardiographic findings in women with severe aortic stenosis following surgical aortic valve replacement or TAVI.

Methods

At 48 European centers, 443 women underwent randomization 1:1, and 420 were treated as randomized. Echocardiograms were available in 356 patients and were analyzed by a core laboratory.

Results

Rates of or greater moderate paravalvular regurgitation was low (<1%) and similar between groups. At 30 days, TAVI was associated with higher mean transprosthetic gradient and smaller aortic valve area, but the rate of severe patient–prosthesis mismatch (3.0 versus 2.6%; P=1) was low and not different between groups. Valve hemodynamics were stable at 1 year. The rate of residual left ventricular hypertrophy (45.3 versus 28.6%; P=0.004) at 1 year was significantly higher with TAVI, whereas the rate of right ventricular systolic dysfunction (14.5 versus 40.7%; P<0.001) and evolution of cardiac damage stage (improved in 21.8 versus 18.1%; worsened in 16.8 versus 47.0%; P=0.001) were better with TAVI.

Conclusions

Among women with severe aortic stenosis, both TAVI and surgical aortic valve replacement achieve excellent valve hemodynamic results with low and similar rates of moderate or greater paravalvular regurgitation or severe patient–prosthesis mismatch. Surgical aortic valve replacement was associated with lower gradients and more pronounced regression of left ventricular hypertrophy, whereas TAVI was associated with better right ventricular systolic function and evolution of cardiac damage stage.

REGISTRATION

URL: https://clinicaltrials.gov/study/NCT04160130; Unique Identifier: NCT04160130.

Nonstandard Abbreviations and Acronyms

AR

aortic regurgitation

AS

aortic stenosis

AVA

aortic valve area

AVR

aortic valve replacement

PARTNER 3

Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low‐Risk Patients With Aortic Stenosis

PASP

pulmonary artery systolic pressure

PPM

patient–prosthesis mismatch

RHEIA

Randomized Research in Women All Comers With Aortic Stenosis

SAVR

surgical aortic valve replacement

SMART

Small Annuli Randomized to Evolut or SAPIEN Trial

TAPSE

tricuspid annular plane systolic excursion

TAVI

transcatheter aortic valve implantation

Clinical Perspective.

What Is New?

• In women with severe aortic stenosis, both transcatheter aortic valve implantation and surgical aortic valve replacement yield excellent clinical and echocardiographic outcomes.

• Surgical aortic valve replacement is associated with better overall valve hemodynamic performance and regression of left ventricular hypertrophy, whereas transcatheter aortic valve implantation is associated with better evolution of right ventricular function and cardiac damage.

What Are the Clinical Implications?

• Transcatheter aortic valve implantation may be preferred in women with severe aortic stenosis, especially in those with preexisting advanced cardiac damage stage (≥2) or right ventricle–pulmonary artery uncoupling.

Among patients with severe aortic stenosis (AS), approximately half are women. ¹ , ² Women with AS have smaller aortic annuli than men and present with less aortic valve calcification but more valvular fibrosis. ³ , ⁴ They are also more likely to display left ventricular (LV) concentric remodeling; a larger extent of diffuse myocardial fibrosis; better preservation of LV ejection fraction; and more paradoxical low‐flow, low‐gradient AS. ³ , ⁴ Because of these distinctive features and modes of disease presentation, women are less likely to be referred for aortic valve replacement (AVR), and less likely to receive AVR treatment. ⁴ , ⁵ In addition, women have been underrepresented in cardiovascular trials, especially in transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) trials in patients with severe AS and low surgical risk. ⁶ , ⁷ , ⁸

The RHEIA (Randomized Research in Women All Comers With Aortic Stenosis) trial, conducted in 12 European countries, was the first prospective, randomized controlled trial comparing outcomes of TAVI with a balloon‐expandable valve versus SAVR with any surgical valve exclusively in women with symptomatic severe AS and demonstrated a significant reduction in the composite of death, stroke, or rehospitalization at 1‐year follow‐up with TAVI compared with SAVR. ⁹

Echocardiography is key to assessing the evolution of cardiac chamber geometry and function following AVR and to determine the bioprosthetic valve hemodynamic performance and its stability during follow‐up. The objectives of this study are (1) to compare echocardiographic findings in women with severe AS following SAVR or TAVI; and (2) to determine the association between echocardiographic parameters at 30 days and clinical outcomes at 1 year.

Methods

The data, methods used in the analysis, and materials used to conduct the research available will be available upon request.

Patient Selection, Study Design, and Management

RHEIA is an investigator‐initiated, randomized clinical trial that randomized women with severe symptomatic AS to TAVI with the balloon‐expandable SAPIEN 3 (or Ultra; Edwards Lifesciences, Irvine, CA) system or SAVR with a commercially available surgical valve. Women were eligible for trial inclusion if they had severe symptomatic AS and both approaches (surgical and transcatheter) were deemed suitable after heart team discussion. Patients with unicuspid, bicuspid, or noncalcified aortic valves, complex coronary artery disease, or other anatomic features that increased the risk of complications with either TAVI or surgery were excluded. The RHEIA trial design and protocol have been previously published. ⁹ , ¹⁰ The RHEIA steering committee was responsible for preparing the design of the trial. The study was approved by the institutional review boards of each participating site, and patients gave informed consent for study participation.

From November 2019 through April 2023, 443 women were enrolled at 48 European centers to TAVI (221 patients) or surgery (222 patients). The assigned procedure was initiated in 420 patients (215 in the TAVI arm and 205 patients in the surgical arm) who composed the as‐treated population.

A total of 185 and 171 patients for the TAVI and SAVR groups, respectively, had 30‐day echocardiographic data available and were included in the present analysis (Figure S1).

Echocardiography Core Laboratory Analyses

Transthoracic echocardiograms of the as‐treated population were obtained at baseline and at 30 days and 1 year after the procedure and were analyzed by an independent echocardiography core laboratory based at the Québec Heart and Lung Institute. Image acquisition and analysis were performed according to the American Society of Echocardiography standards for echocardiography core laboratories, ¹¹ and methods for echocardiographic measurements in the RHEIA trial were the same as those used for the PARTNER 3 (Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low‐Risk Patients With Aortic Stenosis) trial, which have been previously described. ¹² , ¹³

Methods, formulas, and definitions for echocardiographic parameters, including aortic valve hemodynamics and LV and right ventricular (RV) geometry and function, are outlined in the Supporting Information Methods.

Patient–prosthesis mismatch (PPM), high residual gradient, and intended valve hemodynamic performance were defined according to Valve Academic Research 3 standardized definitions (Supporting Information Methods). ¹⁴ Aortic regurgitation (AR) was assessed before and after the procedure using a multiparameter integrative approach as previously described ¹⁵ and was graded according to a 3‐class scheme as follows: mild, moderate, and severe. ¹⁶

Beyond the standard measurements that are described in the Supporting Information Methods, the valvulo‐arterial impedance (Z _va) was calculated to estimate the total LV hemodynamic load: Z _va=(systolic blood pressure+mean transvalvular gradient)/stroke volume indexed to body surface area. ¹⁷ Tricuspid annulus plane systolic excursion (TAPSE) was measured on 2‐dimensional images in the 4‐chamber view to assess RV systolic function. ¹² Pulmonary artery systolic pressure (PASP) was assumed to be equivalent to the RV systolic pressure in the absence of pulmonic stenosis or RV outflow tract obstruction. RV systolic dysfunction was defined as TAPSE ≤1.6 cm. RV–pulmonary artery (PA) coupling ratio, which refers to the relationship between RV contractility and afterload, was calculated as TAPSE/PASP. RV‐PA uncoupling was defined as a TAPSE/PASP ratio <0.50 mm/mm Hg. ¹⁸ , ¹⁹ Patients were further categorized into 5 stages of extravalvular cardiac damage, as previously described (Supporting Information Methods). ²⁰

Hemodynamic valve deterioration from 30 days to 1‐year follow‐up was defined according to Valve Academic Research 3 ¹⁴ (Supporting Information Methods), and the percentage of patients alive with normally functioning valves (ie, free of stage 2 or 3 hemodynamic valve deterioration) was also evaluated.

Statistical Analysis

Continuous variables are presented as mean±SD or median with interquartile range and were compared using Student’s t test or the Wilcoxon rank‐sum test. Categorical variables are presented as proportions and were compared using the Fisher exact test. Violin plots were used to present the distribution of the echocardiographic parameters at the different time points in the TAVI and SAVR groups. The comparisons of continuous echocardiographic variables in these plots were performed using generalized estimating equations models, taking into account the data from all time points simultaneously. Spaghetti plots were used to present the changes in cardiac damage staging from baseline to 1‐year follow‐up.

The composite primary end point of the RHEIA trial was all‐cause death, stroke, and rehospitalization for valve or procedure‐related symptoms or worsening heart failure within 1 year of randomization. Time‐to‐event outcomes were evaluated using Kaplan–Meier estimates with the log‐rank test and Cox proportional hazard model. The proportional hazard assumption was assessed by the Schoenfeld residuals test and was fulfilled for all models. P values <0.05 were considered significant. Given the exploratory character of the study, no corrections for multiple testing were applied.

All statistical analyses were performed using R version 4.5.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Clinical and Echocardiographic Characteristics

Baseline clinical characteristics for the as‐treated groups are displayed in Table S1, with no significant differences observed between the TAVI and SAVR groups. Echocardiographic parameters at baseline, 30 days, and 1 year are shown in Tables 1 and 2.

Table 1.

Aortic Valve Hemodynamics With TAVI Versus SAVR at Baseline, 30 Days, and 1‐Year Follow‐Up

Variables	Baseline			30 d			1 y
	TAVI (n=185)	SAVR (n=171)	P value	TAVI (n=185)	SAVR (n=171)	P value	TAVI (n=185)	SAVR (n=171)	P value
AV hemodynamics
Vpeak, cm/s, mean±SD	427.7±61.9	428.6±57.2	0.893	240.3±43.6	217.1±38.3	<0.001	242.1±43.9	224.8±41.3	<0.001
Mean gradient, mm Hg, mean±SD	47.9±13.7	47.7±13.9	0.989	13.6±5	10.9±4	<0.001	14±5.6	11.8±4.4	<0.001
High residual gradient (>20 mm Hg), n (%)	…	…	…	20/185 (10.8)	5/171 (2.9)	0.004	19/163 (11.7)	7/148 (4.7)	0.039
AVA, cm2, mean±SD	0.81±0.25	0.84±0.2	0.786	1.81±0.42	1.95±0.49	0.007	1.78±0.47	1.88±0.46	0.082
AVAi, cm2/m2, mean±SD	0.46±0.14	0.46±0.11	0.769	1.02±0.25	1.07±0.27	0.093	1.00±0.27	1.04±0.27	0.139
Severe PPM, n (%)	—	—	—	5/167 (3.0)	4/156 (2.6)	1	7/149 (4.7)	5/137 (3.6)	0.77
Doppler velocity index, mean±SD	0.22±0.06	0.22±0.04	0.409	0.47±0.09	0.52±0.11	<0.001	0.46±0.1	0.49±0.1	0.016
Moderate or greater total AR, n (%)	9/151 (6)	6/131 (4.6)	0.791	1/157 (1.3)	0	1	1/160 (0.6)	0	1
Moderate or greater paravalvular AR, n (%)	…	…	…	1/157 (0.6)	0	1	1/160 (0.6)	0	1
Moderate or greater transvalvular AR, n (%)	9/151 (6)	6/131 (4.6)	0.791	0	0	1	0	0	1
Intended valve hemodynamic performance	…	…	…	128/152 (84.2)	132/137 (96.4)	0.001	129/151 (85.4)	129/137 (94.2)	0.020

AR indicates aortic regurgitation; AV, aortic valve, AVA, aortic valve area; AVAi, indexed aortic valve area; PPM, patient–prosthesis mismatch; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation; and V_peak, peak aortic jet velocity.

Table 2.

Echocardiographic LV and RV Geometry and Function With TAVI Versus SAVR at Baseline, 30 Days, and 1‐Year Follow‐Up

Variables	Baseline			30 d			1 y
	TAVI (n=185)	SAVR (n=171)	P value	TAVI (n=185)	SAVR (n=171)	P value	TAVI (n=185)	SAVR (n=171)	P value
LV geometry and function
LV end‐diastolic diameter, cm, mean±SD	4.72±0.56	4.74±0.55	0.845	4.72±0.5	4.56±0.54	0.01	4.75±0.56	4.62±0.51	0.045
LV end‐systolic diameter, cm, mean±SD	2.79±0.62	2.81±0.6	0.734	2.83±0.6	2.82±0.55	0.874	2.84±0.64	2.76±0.62	0.243
LV mass index, g/m2, mean±SD	103.2±29.2	100.5±23.3	0.445	94.4±24.2	86±22.8	0.005	92.4±24.9	83.4±22.1	0.001
LV hypertrophy ≥91 g/m2, n (%)	90/148 (60.8)	76/127 (59.8)	0.902	71/151 (47)	49/136 (36)	0.072	67/148 (45.3)	40/140 (28.6)	0.004
Relative wall thickness, mean±SD	0.46±0.09	0.45±0.08	0.752	0.43±0.08	0.44±0.09	0.416	0.42±0.10	0.41±0.08	0.403
LV ejection fraction by Simpson, %, mean±SD	66.9±9.7	68.3±8	0.298	67±8.9	67.3±8.7	0.936	66.9±9.3	68.1±8.6	0.167
LV ejection fraction <50%, n (%)	7/143 (4.9)	5/125 (4)	0.776	7/150 (4.7)	3/135 (2.2)	0.342	8/150 (5.3)	6/132 (4.5)	0.791
LV stroke volume, mL, mean±SD	81.1±17.7	85.1±17.7	0.063	86.4±16.6	80.7±16.9	0.005	87.9±17.5	85.7±16.2	0.271
LV stroke volume index, mL/m2, mean±SD	45.6±10.2	47.1±10.6	0.364	48.6±9.7	44.7±9.6	0.001	49.2±10.3	47.6±9.8	0.065
Low‐flow (stroke volume index <35 mL/m2), n (%)	20/146 (13.7)	14/127 (11)	0.583	12/146 (8.2)	18/137 (13.1)	0.246	9/149 (6)	11/137 (8)	0.644
Z va, mm Hg/ml/m2	4.33±1.01	4.14±0.95	0.241	3.32±0.72	3.48±0.78	0.170	3.37±0.99	3.36±0.84	0.890
Moderate or greater MR, n (%)	3/147 (2)	0/127 (0)	0.251	3/155 (1.9)	4/145 (2.8)	0.715	1/157 (0.6)	3/139 (2.2)	0.345
LV diastolic dysfunction
Normal, n (%)	14/123 (11.4)	12/103 (11.7)	1.000	45/124 (36.3)	39/116 (33.6)	0.686	40/121 (33.1)	46/110 (41.8)	0.176
Grade I, n (%)	50/123 (40.7)	48/103 (46.6)	0.419	38/124 (30.6)	41/116 (35.3)	0.493	49/121 (40.5)	34/110 (30.9)	0.134
Grade II, n (%)	56/123 (45.5)	41/103 (39.8)	0.420	40/124 (32.3)	34/116 (29.3)	0.676	32/121 (26.4)	29/110 (26.4)	1.000
Grade III, n (%)	3/123 (2.4)	2/103 (1.9)	1.000	1/124 (0.8)	2/116 (1.7)	0.611	0/121 (0)	1/110 (0.9)	0.476
RV function
TAPSE, cm, mean±SD	2.13±0.46	2.23±0.39	0.084	2.09±0.49	1.49±0.47	<0.001	2.08±0.44	1.69±0.45	<0.001
RV systolic dysfunction (TAPSE <1.6 cm), n (%)	16/141 (11.3)	7/128 (5.5)	0.125	27/152 (17.8)	92/137 (67.2)	<0.001	21/145 (14.5)	55/135 (40.7)	<0.001
Moderate or greater TR, n (%)	3/129 (2.3)	2/117 (1.7)	1.000	2/141 (1.4)	4/128 (3.1)	0.428	3/143 (2.1)	11/131 (8.4)	0.026
PASP, mm Hg, mean±SD	32.7±11.8	33±10.3	0.804	30.3±7.5	28.1±8.4	0.032	29.5±8.9	33.3±22.5	0.086
RV‐PA coupling (TAPSE/PASP, mm/mm Hg), mean±SD	0.70±0.34	0.74±0.26	0.396	0.73±0.26	0.59±0.36	0.001	0.78±0.32	0.57±0.21	<0.001
RV‐PA uncoupling (<0.50 mm/mm Hg), n (%)	23/95 (24.2)	16/77 (20.8)	0.715	14/108 (13)	42/98 (42.9)	<0.001	13/104 (12.5)	37/106 (34.9)	<0.001

LV indicates left ventricular; MR, mitral regurgitation; PASP, pulmonary artery systolic pressure; RV, right ventricular; RV‐PA, right ventricular–pulmonary artery coupling; SAVR, surgical aortic valve replacement; TAPSE, tricuspid annular plane systolic excursion; TAVI, transcatheter aortic valve implantation; TR, tricuspid regurgitation; and Z _va, valvuloarterial impedance.

At baseline, there were no significant differences between patients undergoing TAVI and patients undergoing SAVR for aortic valve hemodynamics (ie, mean gradients and AVA; Table 1 and Figure 1), LV geometry, or systolic and diastolic function (Table 2). There was a trend toward better RV function (TAPSE: 2.23±0.39 versus 2.13±0.46 cm; P=0.08) among patients undergoing SAVR (Table 2).

Figure 1. Evolution of valve hemodynamics following TAVI and SAVR.

Violin plots of (A) aortic valve area, (B) mean gradient, and (C) Doppler velocity index at baseline, 30 days, and 1 year after SAVR (red) or TAVI (blue). The distribution is shown by the width of each violin; the dashed line marks the mean, and the 3 solid bars indicate the 25th percentile, median, and 75th percentile. Values represent the distribution of each metric at each time point. Between‐group P values are displayed when significant. NS indicates nonsignificant; SAVR, surgical aortic valve replacement; and TAVI, transcatheter aortic valve implantation.

Bioprosthetic Valve Hemodynamic Performance

At 30 days after the procedure, the mean transprosthetic gradient (TAVI: 13.6±5 versus SAVR: 10.9±4.0; P<0.001) and the rate of high residual gradient (mean gradient >20 mm Hg) (10.8% versus 2.9%; P=0.004) were significantly higher in TAVI versus SAVR (Table 1, Figure 1B and 2A). AVA (1.81 ± 0.42 versus 1.95 ± 0.49; P=0.007), and Doppler velocity index (0.47±0.09 versus 0.52±0.11; P<0.001) was smaller with TAVI (Table 1, Figures 1A and 1C). The results of valve hemodynamic performance were stable with similar differences between groups at 1 year (Table 1, Figure 1). Results were consistent when using a paired analysis (Figure S2).

Figure 2. Valve hemodynamic performance and nonstructural valve dysfunction following TAVI and SAVR.

Bar plots showing valve‐related outcomes at 30 days and 1 year after TAVI or SAVR. (A) Proportion of patients with a residual mean gradient >20 mm Hg. (B) Distribution of prosthesis–patient mismatch severity, categorized as none, moderate, or severe. (C) Distribution of paravalvular aortic regurgitation severity, categorized as none/trace, mild, and moderate. (D) Proportion of patients achieving the intended valve hemodynamic performance (yes versus no). Values represent the percentage of patients in each category. Between‐group P values are displayed when significant. NS indicates nonsignificant; SAVR, surgical aortic valve replacement; and TAVI, transcatheter aortic valve implantation.

The rates of moderate or greater paravalvular AR at 30 days were low and not statistically different between the TAVI versus SAVR groups (0.6 versus 0%, P=1.0) and were stable at 1‐year follow‐up. However, the rates of mild paravalvular AR were higher in the TAVI group (14 versus 2.8%; P<0.001; Figure 2C). There were no cases of moderate or greater transvalvular AR in either group (Table 1, Figure S3). The rates of severe PPM were low and not different between groups at 30 days (3.0 versus 2.6%; P=1; Table 1, Figure 2B). The rates of intended valve hemodynamic performance were lower with patients undergoing TAVI versus patients undergoing SAVR at both 30 days (84.2 versus 96.4%; P=0.001) and 1 year (85.4 versus 94.2%; P=0.020; Table 1, Figure 2D).

LV Geometry and Function

At 1 year after the procedure, LV mass index (TAVI: 92.4±24.9 versus SAVR: 83.4±22.1 g/m²; P=0.001; Figure 3A) and LV hypertrophy (45.3 versus 28.6%; P=0.004) were significantly higher with TAVI versus SAVR (Table 2). In the whole cohort (TAVI and SAVR groups pooled), severe PPM and high residual gradient at 30 days were not associated with residual LV hypertrophy at 1 year, but presence of mild or greater AR was significantly associated (58.3 versus 35.3%). In multivariable logistic regression analysis including mild or greater AR, severe PPM, and high residual gradient at 30 days, only mild or greater AR was independently associated with presence of residual LV hypertrophy at 1 year (odds ratio, 2.60 [95% CI, 1.10–6.34]; P=0.03). LV ejection fraction did not change significantly after AVR and was similar between groups at all time points (Table 2, Figure 3B). LV indexed stroke volume decreased significantly in patients undergoing SAVR from baseline to 30 days, showing significantly lower values compared with TAVI (48.6±9.7 versus 44.7±9.6 mL/m²; P=0.001; Table 2, Figure 3C). However, this difference was no longer significant at 1‐year follow‐up (49.2±10.3 versus 47.6±9.8 mL/m²; P=0.07; Table 2, Figure 3C). There was a trend toward lower Z _va with TAVI versus SAVR (3.32±0.72 versus 3.48±0.78 mm Hg/mL/m²; P=0.17; Table 2, Figure 3D) at 30 days that was no longer present at 1‐year follow‐up (3.37±0.99 versus 3.36±0.84 mm Hg/mL/m²; P=0.89; Table 2, Figure 3D). Results were consistent in paired analyses for LV mass index, LV ejection fraction, and Z _va, while no significant differences were observed between TAVI versus SAVR for LV indexed stroke volume at 30 days and 1 year (Figure S4). LV diastolic function was similar between groups at both 30 days and 1 year (Table 2).

Figure 3. Evolution of LV geometry and function following TAVI and SAVR.

Violin plots of (A) LV mass index, (B) LVEF, (C) stroke volume index, and (D) valvuloarterial impedance at baseline, 30 days, and 1 year after SAVR (red) or TAVI (blue). The distribution is shown by the width of each violin; the dashed line marks the mean, and the 3 solid bars indicate the 25th percentile, median, and 75th percentile. Values represent the distribution of each metric at each time point. Between‐group P values are displayed when significant. LV indicates left ventricle; LVEF, left ventricle ejection fraction; NS, nonsignificant; SAVR, surgical aortic valve replacement; and TAVI, transcatheter aortic valve implantation.

RV Function and Coupling

RV function decreased significantly after AVR among patients undergoing SAVR leading to significantly lower TAPSE compared with TAVI at both 30 days (TAVI: 2.09±0.49 versus SAVR: 1.49±0.47 cm; P<0.001) and 1‐year follow‐up (2.08±0.44 versus 1.69±0.45 cm, P<0.001; Table 2, Figure 4A). Patients undergoing SAVR also showed a lower RV‐PA coupling ratio at both 30 days (0.73±0.26 versus 0.59±0.36 mm/mm Hg; P=0.001) and 1‐year follow‐up (0.78±0.32 versus 0.57±0.21 mm/mm Hg; P<0.001; Table 2, Figure 4B). The 1‐year rates of RV systolic dysfunction (14.5% versus 40.7%; P<0.001) and RV‐PA uncoupling (12.5% versus 34.9%, P<0.001) were thus higher with SAVR (Table 2). SAVR was associated with a higher rate of moderate or greater tricuspid regurgitation at 1 year (2.1% versus 8.4%; P=0.026; Table 2).

Figure 4. Evolution of RV function parameters following TAVI and SAVR.

Violin plots of RV function parameters at baseline, 30 days, and 1 year after SAVR (red) or TAVI (blue). A, TAPSE. B, RV‐PA coupling. The distribution is shown by the width of each violin; the dashed line marks the mean, and the 3 solid bars indicate the 25th percentile, median, and 75th percentile. Values represent the distribution of each metric at each time point. Between‐group P values are displayed when significant. NS indicates nonsignificant; RV, right ventricle; PASP, pulmonary artery systolic pressure; RV‐PA, right ventricular–pulmonary artery coupling; SAVR, surgical aortic valve replacement; TAPSE, tricuspid annular plane systolic excursion; and TAVI, transcatheter aortic valve implantation.

Cardiac Damage Staging

Figure 5 shows the evolution of the cardiac damage stage from baseline to 1 year in TAVI (Figure 5A) and in SAVR (Figure 5B). The distributions of patients with improved (21.8% in TAVI versus 18.1% in SAVR), unchanged (61.4 versus 34.9%), or worsened (16.8 versus 47.0%) cardiac damage stage significantly differed (P<0.001) between treatment groups (Figure 5C). At 1‐year follow‐up, TAVI was associated with lower rates of advanced (stages 3–4) cardiac damage (18.8% versus 47.0%; P<0.001; Figure 5A and 5B).

Figure 5. Evolution of cardiac damage stages before and 1 year following TAVI and SAVR.

Spaghetti plots showing cardiac damage stages from baseline to 1‐year follow‐up after (A) TAVI and (B) SAVR. Each flow represents the proportion of patients moving between stages, with flow width proportional to the number of patients. Percentages at the left and right margins indicate the distribution of stages at baseline and at 1 year, respectively. C, Bar plots showing cardiac damage stage changes 1 year after TAVI or SAVR. Patients are categorized as improved (green), unchanged (yellow), or worsened (red) at follow‐up. Values represent the percentage of patients in each category. CD indicates cardiac damage stage; SAVR, surgical aortic valve replacement; and TAVI, transcatheter aortic valve implantation.

Bioprosthetic Valve Dysfunction and Failure

The 1‐year rates of stage 2 or 3 hemodynamic valve deterioration (1.8 versus 1.4%, P=1.0) and valve reintervention (1.1 versus 0%; P=0.5) were low and not different between the TAVI versus SAVR arms. The percentage of patients alive and with a normally functioning valve was high and similar in both groups (TAVI: 97.6% versus SAVR: 96.7%; P=0.74).

Association Between Echocardiographic Parameters and Clinical Outcomes

None of the individual echocardiographic parameters measured at 30 days after the procedure was associated with the primary clinical end point at 1 year in the whole cohort (TAVI and SAVR groups pooled; Figure S5). However, cardiac damage stage ≥2 at 30 days was associated with increased risk of the primary end point (cardiac damage stage ≥2: 15.7 versus 6.2%; P=0.05; Figure S5). The superiority of TAVI versus SAVR with regard to the incidence of the primary clinical end point appeared to be more pronounced in the subgroup of patients with cardiac damage stage ≥2 at baseline (20.1% with SAVR versus 7.8% with TAVI; P=0.017) compared with the subgroup with stage <2 (7.1 versus 4.3%; P=0.64; Figure S6). Similar findings were observed in the subgroup of patients with RV‐PA uncoupling, that is, TAPSE/PASP <0.5 mm/mm Hg (25.0% with SAVR versus 4.3% with TAVI; P=0.067) compared with that with TAPSE/PASP ≥0.5 mm/mm Hg (9.8 versus 8.2%; P=0.75; Figure S6).

Discussion

The main findings of this study can be summarized as follows:

1. Among women with severe AS, both TAVI and SAVR achieved excellent valve hemodynamic results with ≈97% of patients alive with a normally functioning valve at 1 year.

2. Mean transvalvular gradient was higher and AVA was smaller with TAVI versus SAVR, but the rate of severe PPM was low (≤3%) and similar between groups.

3. The rate of moderate or greater paravalvular AR was low (<1.0%) and not different between groups, and there was no case of moderate or greater transvalvular AR in both groups. Mild paravalvular AR was more frequent with TAVI versus SAVR.

4. SAVR was associated with greater regression of LV hypertrophy but similar improvement in LV systolic and diastolic dysfunction compared with TAVI.

5. The higher rate of residual LV hypertrophy with TAVI appears to be related to the higher rate of mild paravalvular AR.

6. TAVI was associated with better RV systolic function and RV‐PA coupling and better evolution of overall cardiac damage stage compared with SAVR.

7. The rates of hemodynamic valve deterioration and reintervention at 1 year were low (<2%) in both groups.

8. None of the individual echocardiographic parameters was associated with the primary clinical end point at 1 year. However, the multiparameter integrative staging classification of cardiac damage (≥2) was associated with increased risk of the primary end point.

Bioprosthetic Valve Hemodynamic Performance

In the PARTNER 3 trial, where the population was predominantly composed of men, mean transprosthetic gradients were slightly but significantly higher with TAVI, whereas AVA as well as the rates of severe PPM and high residual gradient were not statistically different between groups. ⁷ , ¹² , ¹³ In the RHEIA trial, which included only women with generally smaller aortic annuli, patients undergoing TAVI also exhibited significantly smaller AVA and indexed AVA and higher rates of high residual gradients compared with SAVR, although the rates of severe PPM were similar between groups.

In line with recent reports on new‐generation balloon‐expandable TAVI devices, the rates of greater than mild residual paravalvular AR were extremely low and comparable to those achieved by surgery. ⁷ , ²¹ The rate of mild paravalvular AR, however, remained higher with TAVI versus SAVR, which is consistent with the results obtained in PARTNER 3. ⁷ , ¹² , ¹³ The lower rate of intended valve hemodynamic performance observed in the TAVI arm in the present study was essentially related to the higher rate of high residual gradient in this arm. However, previous studies that examined the clinical impact of 30‐day valve hemodynamic performance of balloon‐expandable transcatheter heart valves in patients with a small aortic annulus found an association with moderate or greater paravalvular AR but not with high residual gradients (>20 mm Hg) or severe PPM. ¹³ , ²² Consistently, in the present study, we found no association between high residual gradients, severe PPM, or intended valve hemodynamic performance at 30 days and clinical outcomes at 1 year.

The valve hemodynamic function was stable from 30 days to 1 year with low rates of hemodynamic valve deterioration and valve reintervention in both treatment groups. One of the most striking results of this study is that the percentage of patients with a normally functioning valve at 1 year was excellent and similar with both TAVI and SAVR.

LV Geometry and Function

Regression of LV hypertrophy is an important objective of AVR. Women with severe AS generally present with more pronounced LV concentric remodeling and hypertrophy, which is associated with increased risk of death. ²³ In the present study, patients undergoing TAVI experienced less regression of LV hypertrophy at 1 year compared with patients undergoing SAVR. This finding, which was not found in PARTNER 3, ¹² , ¹³ appears to be related to the higher rate of mild paravalvular AR with TAVI. Indeed, women have more pronounced LV concentric remodeling/hypertrophy and a smaller LV cavity compared with men and may thus be more vulnerable to the negative effect of mild AR on LV mass regression. In the RHEIA trial, 55% of the patients had LV hypertrophy at baseline versus 35% in PARTNER 3. Despite the lesser regression of LV hypertrophy with TAVI, the improvement of LV diastolic and systolic dysfunction was similar in both groups.

In the RHEIA trial, mild paravalvular AR at 30 days was associated with a higher rate of residual LV hypertrophy at 1 year. An analysis of the PARTNER 2 trial previously reported that moderate or greater paravalvular AR at 30 days was associated with less regression of LV hypertrophy at 2 years, but the impact of mild AR (versus none/trace) on LV remodeling was not specifically analyzed. ²⁴ Several studies and meta‐analyses reported that mild paravalvular AR may have an impact on long‐term clinical outcomes. ²⁵ , ²⁶ Hence, mild paravalvular AR may not be necessarily benign from both a hemodynamic and a clinical standpoint. The present study suggests that even a mild paravalvular AR may have a signficant impact on the regression of LV hypertrophy in women with severe AS. Indeed, women with severe AS generally have small LV cavities with pronounced concentric remodeling, often advanced LV diastolic dysfunction and reduced LV compliance (see Table 2). These patients may thus be more vulnerable to the effect of volume overload, and in this context even a mild volume overload, especially if it is acute, such as paravalvular AR following TAVI, may have a detrimental impact on LV positive remodeling. ²⁷ , ²⁸ These findings are hypothesis generating and should be confirmed in further studies.

RV Systolic Function and Coupling

SAVR was associated with a marked deterioration in RV longitudinal systolic function and RV‐PA coupling and higher rates of moderate or greater tricuspid regurgitation at 30 days, which persisted at 1 year, whereas RV function was well preserved with TAVI. Although RV systolic dysfunction or RV‐PA uncoupling at 30 days was not associated with 1‐year outcomes in the present study, previous analyses from PARTNER 2 and PARTNER 3 have demonstrated the impact of this early decline in RV systolic function associated with SAVR on clinical outcomes. ¹² , ¹³ , ¹⁹ The mechanisms that may explain the deterioration of RV function associated with SAVR include suboptimal protection of the RV during cardioplegia, perioperative episodes of hypertension, uncoupling of the RV and pericardial sac attributable to pericardiectomy, and coronary air embolism. ²⁹ , ³⁰ , ³¹ , ³² , ³³

Some studies suggest that the decline in TAPSE immediately following open‐heart surgery is artifactual and related more to geometric changes due to pericardiectomy rather than true functional change. ³⁴ According to this concept, the reduction in longitudinal function (ie, TAPSE) is transient and is compensated by the increase in radial function, therefore maintaining normal RV ejection fraction. However, as opposed to the LV, the RV has limited capacity to increase its radial function, and the RV ejection fraction is mainly dependent on the longitudinal shortening. Furthermore, in the RHEIA and PARTNER 3 trials, the reduction in TAPSE following SAVR persisted to 1 year and beyond. Some studies using echocardiographic parameters other than TAPSE confirmed that new onset RV dysfunction is frequent following cardiopulmonary bypass and is independent of the procedural characteristics and of the pericardiectomy. ³⁰ In the PARTNER 2 and PARTNER 3 trials, ¹⁹ the presence of moderate/severe RV dysfunction, defined as TAPSE <1.6 cm at 30 days, was strongly associated with clinical outcomes at 1 and 5 years following aortic valve replacement (SAVR or TAVI). There is thus a strong body of evidence that the reduction in TAPSE following SAVR is physiologically and clinically significant.

Cardiac Damage Staging

TAVI was associated with more favorable evolution of cardiac damage stage compared with SAVR. This finding is mainly driven by the lower rate of new‐onset RV systolic dysfunction, and so of stage 4 cardiac damage and also, to a lesser extent, to the lower rate on new‐onset atrial fibrillation, ⁹ which is a criterion for stage 2 cardiac damage. Among this female population of the RHEIA trial, the rate of worsening of cardiac damage stage was ≈3‐fold higher with SAVR (47%) than with TAVI (16.8%), which appeared higher than in the pooled analysis of PARTNER 2 and PARTNER 3 (2‐fold higher). ³⁵ These findings are clinically relevant given that in the previous PARTNER 2–PARTNER 3 analysis, worsening of cardiac damage stage following AVR was associated with a 2.5‐fold increase in the risk of death and heart failure hospitalization at 2 years. ³⁵

Study Limitations

Echocardiographic data were missing in 15% of the study cohort. TAPSE was the sole parameter used to assess RV function in this study. However, in previous studies, ¹⁹ we reported that TAPSE measured by the 2‐dimensional method is superior to the RV free‐wall strain, tricuspid S′ velocity, and fractional area change with regard to feasibility, reproducibility, and association with clinical outcomes following AVR. In this trial, we did not acquire 3‐dimensional echocardiographic data sets and thus were not able to measure the 3‐dimensional RV ejection fraction.

The duration of the follow‐up is limited to 1 year, and the present results reflect only 1‐year outcomes; longer‐term follow‐up is required to assess and compare structural and hemodynamic valve deterioration in TAVI versus SAVR among women. The results of this study apply only to the enrolled population and TAVI platform used, and we cannot generalize these results to women receiving self‐expanding valves. In the SMART (Small Annuli Randomized to Evolut or SAPIEN Trial), it has been reported that self‐expanding valves with supra‐annular design provide better valve hemodynamics (ie, lower mean transvalvular gradients, larger AVA, and lower rates of severe PPM) and similar rates of paravalvular AR compared with balloon‐expandable valves in a population of patients with a small annulus, which was composed of 75% of women. ³⁶

The subgroup analyses assessing the association between baseline and 30‐day echocardiographic parameters with the primary composite end point should be interpreted with caution, as it is based on post hoc analyses and were underpowered.

Conclusions

Among women with severe AS, both TAVI and SAVR achieved excellent valve hemodynamic results with low and similar rates of moderate or greater paravalvular AR or PPM and ≈97% of patients alive with a normally functioning valve at 1 year. Compared with TAVI, SAVR was associated with lower rates of high residual gradients and mild paravalvular AR and more pronounced regression of LV hypertrophy but similar improvements in LV diastolic and systolic function. However, TAVI was associated with better RV systolic function and RV‐PA coupling, and better evolution of overall cardiac damage stage at 1 year.

Sources of Funding

This was an investigator‐initiated and sponsored trial funded by Edwards Lifesciences.

Disclosures

Dr Bax has received funding from Optimapharm Deutschland GmbH and has received speaker fees from Abbott Vascular and Edwards Lifesciences. The Department of Cardiology, Heart Lung Centre, Leiden University Medical Centre has received unrestricted research grants from Abbott Vascular, Alnylam, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Medtronic, Medis, Pfizer, and Novartis. Dr Bonaros reports speaker honoraria from Edwards Lifesciences and Medtronic and consultant fees from Atricure. Dr Windecker reports research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Braun, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Cleerly Inc., Cordis Medical, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Farapulse Inc., Fumedica, GE Medical Systems, Gebro Pharma, Guerbet, Idorsia, Inari Medical, InfraRedx, Janssen‐Cilag, Johnson & Johnson, Medalliance, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Neucomed, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pharming Tech, Pfizer, Philips AG, Polares, Regeneron, Sanofi‐Aventis, Servier, Siemens Healthcare, Sinomed, SMT Sahajan and Medical Technologies, Terumo, Vifor, V‐Wave, and Zoll Medical. He has served as an advisory board member or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V‐Wave, with payments to the institution but no personal payments. He is also a member of the steering/executive committee group of several investigator‐initiated trials that receive funding from industry without impact on his personal remuneration. Dr Messika‐Zeitoun reports grants from Edwards Lifesciences. W.W. and Dr Rakova are employees of Edwards Lifesciences. Dr Tchétché reports consultant fees from Abbott Vascular, Boston Scientific, Edwards LifeSciences, Medtronic, and Venus MedTech; minor shares from Pi‐Cardia, T‐Heart, and Rampart IC and Electroducer. P. Pibarot has received institutional funding from Edwards Lifesciences, Medtronic, Pi‐Cardia, Cardiac Success, and Roche Diagnostics for echocardiography core laboratory analyses, for which he received no personal compensation. Dr Silva, Dr Alperi, Dr Zanuttini, Dr Théron, Dr Camacho, Dr Dahou, S. Hecht, Dr Bramlage, and Dr Eltchaninoff have no potential conflict of interest to disclose. The other authors have nothing to disclose.

Supporting information

Data S1