Association Between Early Left Ventricular Ejection Fraction Improvement After Transcatheter Aortic Valve Replacement and 5-Year Clinical Outcomes

Dhaval Kolte; Bhaskar Bhardwaj; Michael Lu; Maria C Alu; Jonathan J Passeri; Ignacio Inglessis; Gus J Vlahakes; Santiago Garcia; David J Cohen; Brian R Lindman; Susheel Kodali; Vinod H Thourani; Melissa A Daubert; Pamela S Douglas; Wael Jaber; Philippe Pibarot; Marie-Annick Clavel; Igor F Palacios; Martin B Leon; Craig R Smith; Michael J Mack; Sammy Elmariah

doi:10.1001/jamacardio.2022.2222

. 2022 Jul 27;7(9):934–944. doi: 10.1001/jamacardio.2022.2222

Association Between Early Left Ventricular Ejection Fraction Improvement After Transcatheter Aortic Valve Replacement and 5-Year Clinical Outcomes

Dhaval Kolte ¹, Bhaskar Bhardwaj ², Michael Lu ³, Maria C Alu ^4,⁵, Jonathan J Passeri ⁶, Ignacio Inglessis ⁶, Gus J Vlahakes ⁷, Santiago Garcia ⁸, David J Cohen ^4,⁹, Brian R Lindman ¹⁰, Susheel Kodali ^4,⁵, Vinod H Thourani ¹¹, Melissa A Daubert ¹², Pamela S Douglas ¹², Wael Jaber ¹³, Philippe Pibarot ¹⁴, Marie-Annick Clavel ¹⁴, Igor F Palacios ⁶, Martin B Leon ^4,⁵, Craig R Smith ^4,⁵, Michael J Mack ¹⁵, Sammy Elmariah ^6,^✉

¹Cardiology Division, Massachusetts General Hospital/Harvard Medical School, Boston

²Division of Cardiovascular Medicine, University of Missouri, Columbia

³Edwards Lifesciences, Irvine, California

⁴Cardiovascular Research Foundation, New York, New York

⁵Division of Cardiology, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York

⁶Cardiology Division, Massachusetts General Hospital/Harvard Medical School, Boston

⁷Division of Cardiac Surgery, Massachusetts General Hospital/Harvard Medical School, Boston

⁸Minneapolis Heart Institute Foundation, Minneapolis, Minnesota

⁹St. Francis Hospital and Heart Center, Roslyn, New York

¹⁰Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

¹¹Department of Cardiovascular Surgery, Piedmont Heart Institute, Atlanta, Georgia

¹²Division of Cardiology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina

¹³Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio

¹⁴Department of Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec–Université Laval, Quebec City, Quebec, Canada

¹⁵Department of Cardiothoracic Surgery, Baylor University Medical Center, Dallas, Texas

Accepted for Publication: May 30, 2022.

Published Online: July 27, 2022. doi:10.1001/jamacardio.2022.2222

^✉

Corresponding Author: Sammy Elmariah, MD, MPH, Massachusetts General Hospital, 55 Fruit St, GRB 800, Boston, MA 02114 (selmariah@mgh.harvard.edu).

Author Contributions: Drs Kolte and Elmariah had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kolte, Passeri, Inglessis, Cohen, Thourani, Pibarot, Palacios, Leon, Smith, Mack, Elmariah.

Acquisition, analysis, or interpretation of data: Kolte, Bhardwaj, Lu, Alu, Vlahakes, Garcia, Lindman, Kodali, Thourani, Daubert, Douglas, Jaber, Pibarot, Clavel, Palacios, Leon, Smith.

Drafting of the manuscript: Kolte, Vlahakes, Palacios.

Critical revision of the manuscript for important intellectual content: Kolte, Bhardwaj, Lu, Alu, Passeri, Inglessis, Garcia, Cohen, Lindman, Kodali, Thourani, Daubert, Douglas, Jaber, Pibarot, Clavel, Palacios, Leon, Smith, Mack, Elmariah.

Statistical analysis: Lu.

Obtained funding: Leon.

Administrative, technical, or material support: Alu, Vlahakes, Daubert, Jaber, Smith.

Supervision: Kolte, Inglessis, Garcia, Thourani, Douglas, Palacios, Leon, Elmariah.

Conflict of Interest Disclosures: Dr Kolte reported grants from the National Heart, Lung, and Blood Institute outside the submitted work. Dr Alu reported institutional research support from Edwards Lifesciences during the conduct of the study and from Abbott outside the submitted work. Dr Passeri reports grants and personal fees from Edwards Lifesciences and personal fees from Medtronic. Dr Garcia has received institutional research grants from Boston Scientific, Medtronic, Abbott Vascular, and Edwards Lifesciences; serves as a consultant to Abbott Vascular, Neochord, Medtronic, and Edwards Lifesciences; and serves as a proctor for Edwards Lifesciences. Dr Cohen has received research grant support from Edwards Lifesciences, Medtronic, Abbott, and Boston Scientific and has received consulting fees from Edwards Lifesciences, Medtronic, Abbott, and Boston Scientific. Dr Lindman has served on the scientific advisory board for Roche Diagnostics, received research grants from Edwards Lifesciences and Roche Diagnostics, and consulted for Medtronic outside the submitted work. Dr Kodali reported institutional research grants from Edwards Lifesciences, Medtronic, and Abbott; grants from Edwards Lifesciences, Medtronic, Boston Scientific, Abbott Vascular, and Jenavalve; personal fees from Tricares, Triflo, Phillips, Admedus, and Dura Biotech, consulting fees from Abbott, Admedus, and Meril Lifesciences; equity from Biotrace Medical, MicroInterventional Devices, Thubrikar Aortic Valve Inc, Supira, Adona, Tioga, and X-Dot outside the submitted work. Dr Thourani has received grant support and consulting honoraria from Abbott Vascular, Allergen, Boston Scientific, Cryolife, Edwards Lifesciences, Gore Vascular, and Jenavalve. Dr Daubert reported institutional grant support from Edwards Lifesciences and consulting fees from Bayer. Dr Jaber has core laboratory contracts with Edwards Lifesciences through the Cleveland Clinic C5 with no personal compensation, consultant fees from Pfizer, and grants from Boston Scientific during the conduct of the study. Dr Pibarot reported institutional grants from Edwards Lifesciences during the conduct of the study and grants from Medtronic Contract and Pi-Cardia outside the submitted work. Dr Clavel reported grants from Edwards Lifesciences with no direct compensation and grants from Medtronic outside the submitted work. Dr Leon has received grant support, paid to his institution, from Edwards Lifesciences, Medtronic, Abbott, and Boston Scientific and advisory board fees from Medtronic, Abbott, Boston Scientific, Gore, and Meril Life Sciences. Dr Mack is the co–principal investigator of the trials supported by Edwards Lifesciences, Abbott, and Medtronic all uncompensated during the conduct of the study. Dr Elmariah reported grants from the American Heart Association, National Institutes of Health, Edwards Lifesciences, Medtronic, and Svelte Medical and has received consulting fees from Medtronic and AstraZeneca outside the submitted work. No other disclosures were reported.

Funding/Support: The Placement of Aortic Transcatheter Valves (PARTNER) trials and registries and this analysis were supported by Edwards Lifesciences.

Role of the Funder/Sponsor: Edwards Lifesciences was involved 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.

^✉

Corresponding author.

PMCID: PMC9330296 PMID: 35895046

This cohort study examines the association between early left ventricular ejection fraction (LVEF) improvement and 5-year clinical outcomes after transfemoral transcatheter aortic valve replacement (TAVR) in high- or intermediate-risk patients with symptomatic severe aortic stenosis and LVEF less than 50%.

Key Points

Question

What is the prognostic significance of left ventricular ejection fraction (LVEF) improvement after transcatheter aortic valve replacement (TAVR)?

Findings

In this cohort study of 659 high- or intermediate-risk patients with symptomatic severe aortic stenosis and LVEF less than 50% undergoing transfemoral TAVR, 1 in 3 experienced early LVEF improvement (defined as ≥10 percentage points increase over baseline LVEF at 30 days). Early LVEF improvement after TAVR was associated with lower 5-year all-cause death and cardiac death.

Meaning

Further studies are needed to understand the pathophysiologic mechanism(s) mediating reduced mortality in patients with early LVEF recovery after TAVR.

Abstract

Importance

In patients with severe aortic stenosis and left ventricular ejection fraction (LVEF) less than 50%, early LVEF improvement after transcatheter aortic valve replacement (TAVR) is associated with improved 1-year mortality; however, its association with long-term clinical outcomes is not known.

Objective

To examine the association between early LVEF improvement after TAVR and 5-year outcomes.

Design, Setting, and Participants

This cohort study analyzed patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 1, 2, and S3 trials and registries between July 2007 and April 2015. High- and intermediate-risk patients with baseline LVEF less than 50% who underwent transfemoral TAVR were included in the current study. Data were analyzed from August 2020 to May 2021.

Exposures

Early LVEF improvement, defined as increase of 10 percentage points or more at 30 days and also as a continuous variable (ΔLVEF between baseline and 30 days).

Main Outcomes and Measures

All-cause death at 5 years.

Results

Among 659 included patients with LVEF less than 50%, 468 (71.0%) were male, and the mean (SD) age was 82.4 (7.7) years. LVEF improvement within 30 days following transfemoral TAVR occurred in 216 patients (32.8%) (mean [SD] ΔLVEF, 16.4 [5.7%]). Prior myocardial infarction, diabetes, cancer, higher baseline LVEF, larger left ventricular end-diastolic diameter, and larger aortic valve area were independently associated with lower likelihood of LVEF improvement. Patients with vs without early LVEF improvement after TAVR had lower 5-year all-cause death (102 [50.0%; 95% CI, 43.3-57.1] vs 246 [58.4%; 95% CI, 53.6-63.2]; P = .04) and cardiac death (52 [29.5%; 95% CI, 23.2-37.1] vs 135 [38.1%; 95% CI, 33.1-43.6]; P = .05). In multivariable analyses, early improvement in LVEF (modeled as a continuous variable) was associated with lower 5-year all-cause death (adjusted hazard ratio per 5% increase in LVEF, 0.94 [95% CI, 0.88-1.00]; P = .04) and cardiac death (adjusted hazard ratio per 5% increase in LVEF, 0.90 [95% CI, 0.82-0.98]; P = .02) after TAVR. Restricted cubic spline analysis demonstrated a visual inflection point at ΔLVEF of 10% beyond which there was a steep decline in all-cause mortality with increasing degree of LVEF improvement. There were no statistically significant differences in rehospitalization, New York Heart Association functional class, or Kansas City Cardiomyopathy Questionnaire Overall Summary score at 5 years in patients with vs without early LVEF improvement. In subgroup analysis, the association between early LVEF improvement and 5-year all-cause death was consistent regardless of the presence or absence of coronary artery disease or prior myocardial infarction.

Conclusions and Relevance

In patients with severe aortic stenosis and LVEF less than 50%, 1 in 3 experience LVEF improvement within 1 month after TAVR. Early LVEF improvement is associated with lower 5-year all-cause and cardiac death.

Introduction

Transcatheter aortic valve replacement (TAVR) is a safe and effective treatment option in patients with symptomatic severe aortic stenosis (AS) across the entire spectrum of surgical risk, including in those with left ventricular (LV) systolic dysfunction.¹ Prior studies have shown that in patients with severe AS and LV dysfunction (LV ejection fraction [LVEF], <40%-50%), approximately half experience an improvement in LVEF (defined as an increase of ≥10% points) within 30 days after TAVR.^2,3,4,5,6 Although the association of baseline LV dysfunction with outcomes following TAVR is controversial, among such patients, failure to improve LVEF portends an increased risk of 1-year mortality and rehospitalization after TAVR.^2,3,7,8 However, prior studies examining the association between LVEF improvement and outcomes are limited by small sample size, inclusion of extreme- or high-risk patients only, inclusion of transapical TAVR, which can adversely affect LVEF improvement after TAVR, and short-term (1-year) follow-up.^2,3,4 Thus, the primary objective of this study was to examine the association between early LVEF improvement and 5-year clinical outcomes after transfemoral TAVR in high- or intermediate-risk patients with symptomatic severe AS and LVEF less than 50%.

Methods

Study Population

The study population was drawn from patients at high or intermediate surgical risk included in the Placement of Aortic Transcatheter Valves (PARTNER) 1, 2, and S3 trials and registries and who underwent transfemoral TAVR from July 2007 and April 2015. Patients who underwent transapical TAVR or surgical aortic valve replacement were excluded from this analysis. The design, inclusion and exclusion criteria, and primary results from these trials and registries have been published previously.^9,10,11 In all cohorts, patients had severe AS, defined as an aortic valve area (AVA) less than 0.8 cm² (or indexed AVA <0.5 cm²/m²) and either a resting or inducible mean gradient more than 40 mm Hg or peak jet velocity more than 4 m/s. All patients were symptomatic with New York Heart Association (NYHA) functional class II or higher. For this analysis, we included only patients who underwent transfemoral TAVR, had baseline LVEF less than 50%, and had 30-day follow-up LVEF assessment by echocardiography. Race and ethnicity data were self-reported. The protocols were approved by the institutional review boards of each participating site, and all patients provided written informed consent. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline to report the findings of this study.

Echocardiographic Assessment

Echocardiograms were analyzed by 5 core laboratories using standardized methodology. LVEF was measured using the biplane Simpson volumetric method combining apical 4- and 2-chamber views. LVEF was also determined by visual estimation (in 5-point increments), and when the definition of the LV endocardial border was not adequate for biplane tracing, was substituted to provide a single combined LVEF determination in all patients. For the present analysis, LV dysfunction was defined as an LVEF less than 50%. Improvement in LVEF was assessed as a dichotomous variable (defined as an increase of ≥10 percentage points over baseline LVEF at 30 days) as well as a continuous variable (defined as degree of LVEF improvement [ΔLVEF] between baseline and 30 days). Because 30 days may be early in the course of recovery of LVEF function following TAVR, we performed a secondary analysis using LVEF improvement at 1 year (increase of ≥10 percentage points over baseline LVEF at 1 year, as well as ΔLVEF between baseline and 1 year). The core laboratories followed the American Society of Echocardiography/European Association for Echocardiography guideline for assessing the severity of native valvular stenosis and regurgitation, LV stroke volume index (SVi), and LV mass index.

Study End Points

The primary end point for this study was all-cause death at 5 years. Secondary end points included cardiac death, noncardiac death, rehospitalization, all-cause death or rehospitalization, cardiac death or rehospitalization, NYHA functional class, and Kansas City Cardiomyopathy Questionnaire Overall Summary score at 5 years. Mortality and rehospitalization end points were adjudicated by independent clinical events committees. Definitions of end points are identical to those reported previously. Rehospitalization was defined as hospital readmission for symptoms of AS and/or complications of the valve procedure.

Statistical Analysis

Baseline characteristics were compared between patients with vs without LVEF improvement. Categorical variables are presented as frequency and percentages and compared using Fisher exact test. Continuous variables are presented as mean (SD) and compared using the t test.

We used multivariable logistic and linear regression models to identify independent predictors of LVEF improvement of 10% points or more and ΔLVEF, respectively, at 30 days following TAVR. The following candidate variables were selected a priori for inclusion in the full multivariable models: age, sex, body mass index (BMI), Society of Thoracic Surgeons (STS) score, NYHA functional class, coronary artery disease (CAD), prior myocardial infarction (MI), prior coronary artery bypass grafting, prior percutaneous coronary intervention, prior balloon aortic valvuloplasty, cerebrovascular disease, peripheral artery disease, hypertension, diabetes, chronic obstructive pulmonary disease, oxygen-dependent lung disease, chronic kidney disease (serum creatinine >2 mg/dL; to convert to micromoles per liter, multiply by 88.4), cancer, hemoglobin, baseline LVEF, LV mass index, LV end-diastolic diameter (LVEDD), SVi, AVA, moderate or severe aortic regurgitation, moderate or severe mitral regurgitation, β-blockers at discharge, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker at discharge, post-TAVR aortic valve (AV) mean gradient (at discharge or 30 days), at least moderate paravalvular leak, need for permanent pacemaker, and new atrial fibrillation. Backward variable selection method was used to derive parsimonious multivariable models, keeping only covariates with P value less than .10 in the final models.

Time-to-event end points are presented as Kaplan-Meier estimates and were compared using log-rank test. Outcomes were assessed between 30 days and 5 years to avoid immortal time bias (ie, inclusion of patients who died within 30 days in the no LVEF improvement group). Multivariable Cox proportional hazards regression models were used to compare outcomes of patients with vs without LVEF improvement (improvement of ≥10% points as well as ΔLVEF). The multivariable models adjusted for variables that were statistically significant on univariate analysis (sex, BMI, STS score, diabetes, prior MI, cancer, and baseline LVEF). Restricted cubic spline curve with 3 knots was used to examine the association between ΔLVEF and all-cause death through 5 years. Association between LVEF improvement of 10% points or more and 5-year all-cause death was examined in the overall TAVR cohort as well as the following prespecified subgroups: age (<80 and ≥80 years), sex (male and female), CAD (yes/no), prior MI (yes/no), STS score (<4, 4-8, and >8), baseline LVEF (≤35% and >35%), baseline AVA (<0.6 and ≥0.6 cm²), baseline aortic valve mean gradient (<50 and ≥50 mm Hg), baseline aortic regurgitation (none/mild and ≥moderate to severe), and baseline mitral regurgitation (none/mild and ≥moderate to severe). Interactions between the above prespecified subgroups and LVEF improvement were examined in the multivariable Cox regression models, adjusting for significant covariates. Secondary analysis was performed to determine the association between LVEF improvement at 1 year post-TAVR and 5-year outcomes. For secondary analyses, outcomes were assessed between 1 and 5 years.

Statistical analyses were performed using SAS statistical software version 9.4 (SAS Institute) and R version 3.6.1 (R Foundation). A 2-sided P value less than .05 was considered statistically significant. No multiplicity adjustment was performed. Analysis took place between August 2020 to May 2021.

Results

Baseline Characteristics

The study included 659 patients with symptomatic severe AS at high or intermediate surgical risk and baseline LVEF less than 50% who underwent transfemoral TAVR. A total of 468 patients (71.0%) were male and 191 (29.0%) were female; 4 (0.6%) were Asian, 23 (3.5%) were Black, 12 (1.8%) were Hispanic, 591 (89.7%) were White, and 29 (4.4%) were of other race; and the mean (SD) age was 82.4 (7.7) years. LVEF improvement, defined as an increase of 10% points or more at 30 days post-TAVR, occurred in 216 patients (32.8%) (eFigure 1 in the Supplement), and 86 patients (13.1%) had LVEF of 50% or more at 30 days post-TAVR. Among patients with LVEF improvement, mean (SD) ΔLVEF was 16.4% (5.7%).

Patients with LVEF improvement were less likely to be male individuals, had higher STS score, lower prevalence of comorbidities such as CAD, prior MI, prior coronary artery bypass grafting, peripheral artery disease, cancer, and atrial fibrillation, lower baseline LVEF and SVi, higher AV mean gradient and AV peak velocity, smaller AVA, and larger LVEDD and LV end-systolic diameter, compared with those without LVEF improvement (Table 1). There were no significant differences in rates of more than mild paravalvular leak, permanent pacemaker implantation, or new atrial fibrillation within 30 days post-TAVR in patients with vs without LVEF improvement.

Table 1. Baseline Characteristics of Patients Undergoing TAVR With vs Without Early LVEF Improvement.

Characteristic	No./total No. (%)		P value
Characteristic	No LVEF improvement (n = 443)	LVEF improvement (n = 216)	P value
Age, mean (SD), y	82.1 (7.9)	83.2 (7.4)	.09
Sex
Male	339/443 (76.5)	129/216 (59.7)	<.001
Female	104/443 (23.5)	87/216 (40.3)	<.001
Race and ethnicity^a
Asian	2/443 (0.4)	2/216 (0.9)	.90
Black	14/443 (3.2)	9/216 (4.2)
Hispanic	8/443 (1.8)	4/216 (1.8)
White	399/443 (90.1)	192/216 (88.9)
Other race	20/443 (4.5)	9/216 (4.2)
BMI, mean (SD)	27.4 (5.6)	27.7 (6.6)	.59
STS score, mean (SD)	8.1 (4.4)	8.9 (4.4)	.02
NYHA class III/IV	382/443 (86.2)	197/216 (91.2)	.08
Hypertension	409/443 (92.3)	189/216 (87.5)	.06
Diabetes	174/443 (39.3)	71/216 (32.9)	.12
Coronary artery disease	367/443 (82.8)	162/216 (75.0)	.02
Prior MI	154/443 (34.8)	46/216 (21.3)	<.001
Prior PCI	163/442 (36.9)	73/216 (33.8)	.49
Prior CABG	190/443 (42.9)	61/216 (28.2)	<.001
Prior BAV	60/443 (13.5)	28/216 (13.0)	.90
Atrial fibrillation	185/416 (44.5)	57/175 (32.6)	.008
Cerebrovascular disease	37/443 (8.4)	20/216 (9.3)	.77
Peripheral artery disease	137/443 (30.9)	50/216 (23.1)	.04
Chronic kidney disease^b	63/442 (14.3)	21/216 (9.7)	.11
COPD	145/443 (32.7)	73/216 (33.8)	.79
Oxygen-dependent lung disease	13/443 (2.9)	10/216 (4.6)	.27
Cancer	146/443 (33.0)	49/216 (22.7)	.007
Katz Activities of Daily Living Index, mean (SD)	5.5 (1.0)	5.2 (1.3)	.002
Hemoglobin, mean (SD), g/dL	12.5 (6.5)	11.9 (1.6)	.09
Albumin <3.5 g/dL	88/418 (21.1)	46/184 (25.0)	.29
Baseline echocardiographic data, mean (SD)
LVEF, %	38.8 (8.4)	35.6 (9.1)	<.001
LV mass, g	266.7 (81.8)	260.5 (74.2)	.34
LV mass index, g/m²	139.3 (39.5)	140.9 (40.0)	.63
LVEDD, cm	5.2 (0.8)	5.0 (0.7)	<.001
LVESD, cm	4.2 (0.9)	4.0 (0.8)	.02
AV peak velocity, cm/s	406.1 (60.6)	418.9 (71.6)	.03
AV mean gradient, mm Hg	39.8 (12.5)	43.0 (15.1)	.006
AV area, cm²	0.7 (0.2)	0.6 (0.2)	.001
LVOT Doppler stroke volume, mL	62.0 (15.8)	58.6 (17.5)	.02
LVOT Doppler Stroke Volume Index, mL/m²	32.5 (8.1)	31.5 (8.6)	.16
≥Moderate AR	41/431 (9.5)	23/210 (11.0)	.58
≥Moderate MR	120/424 (28.3)	54/209 (25.8)	.57
Procedural characteristics
Valve size, mm			<.001
20	7/443 (1.6)	1/216 (0.5)
23	81/443 (18.3)	81/216 (37.5)
26	229/443 (51.7)	97/216 (44.9)
29	126/443 (28.4)	37/216 (17.1)
Valve type			<.001
SAPIEN	84/443 (19.0)	62/216 (28.7)
SAPIEN XT	205/443 (46.3)	68/216 (31.5)
SAPIEN 3	154/443 (34.8)	86/216 (39.8)
Predilation	435/441 (98.6)	214/216 (99.1)	.99
Postdilation	88/441 (20.0)	54/213 (25.4)	.13
Concomitant PCI	3/343 (0.9)	3/166 (1.8)	.40
Need for second THV	7/443 (1.6)	1/216 (0.5)	.28
Discharge medications
β-Blocker	317/443 (71.6)	156/216 (72.2)	.93
ACE inhibitor/ARB	234/443 (52.8)	115/216 (53.2)	.93
Procedural complications within 30 d
PPM	36/443 (8.1)	11/216 (5.1)	.20
New atrial fibrillation	21/443 (4.7)	9/216 (4.2)	.84
>Mild PVL	39/434 (9.0)	19/213 (8.9)	>.99
30-d Post-TAVR echocardiographic data
AV gradient, mean (SD), mm Hg	9.6 (3.95)	10.1 (3.40)	.10
Severe prosthesis-patient mismatch^c	63/429 (14.7)	22/208 (10.6)	.17
ΔLVEF (30-d change from baseline), mean (SD), %	1.1 (5.4)	16.4 (5.7)	<.001

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Abbreviations: ACE, angiotensin-converting enzyme; AR, aortic regurgitation; ARB, angiotensin II receptor blocker; AV, aortic valve; BAV, balloon aortic valvuloplasty; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; LVOT, left ventricular outflow tract; MI, myocardial infarction; MR, mitral regurgitation; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PPM, permanent pacemaker; PVL, paravalvular leak; STS, Society of Thoracic Surgeons; TAVR, transcatheter aortic valve replacement; THV, transcatheter heart valve.

SI conversion factors: To convert albumin to grams per liter, multiply by 10; creatinine to micromoles per liter, multiply by 88.4; hemoglobin to grams per liter, multiply by 10.

^{^a}

Race and ethnicity data were self-reported.

^{^b}

Serum creatinine >2 mg/dL.

^{^c}

Defined as indexed effective orifice area <0.65 cm²/m².

Baseline characteristics stratified by sex and LVEF improvement are shown in eTables 1 to 4 in the Supplement. Baseline characteristics of male and female individuals with vs without early LVEF improvement following TAVR were consistent with those of the overall cohort (eTables 1 and 2 in the Supplement). Compared with male individuals, female individuals had higher STS score, lower prevalence of CAD, prior MI, prior percutaneous coronary intervention, prior coronary artery bypass grafting, and chronic obstructive pulmonary disease, lower Katz index, lower hemoglobin, higher baseline LVEF, higher AV mean gradient and AV peak velocity, smaller AVA, smaller LVEDD and LV end-systolic diameter, and higher prevalence of moderate or severe mitral regurgitation (eTables 3 and 4 in the Supplement). Female individuals were more likely to undergo TAVR with a smaller valve size and had higher 30-day AV mean gradient but had similar rates of severe prosthesis-patient mismatch compared with male individuals. These differences in baseline, procedural, and postprocedural characteristics between male vs female individuals were consistent among patients with and without early LVEF improvement following TAVR (eTables 3 and 4 in the Supplement).

Multivariable Predictors of Early LVEF Improvement After TAVR

In multivariable analysis, prior MI, diabetes, cancer, higher baseline LVEF, larger LVEDD, and larger AVA were associated with lower likelihood of early LVEF improvement, whereas higher BMI and higher SVi were associated with increased odds of early LVEF improvement after TAVR (Table 2). When LVEF improvement was modeled as a continuous variable, prior MI, prior coronary artery bypass grafting, hypertension, cancer, higher baseline LVEF, larger LVEDD, and lower post-TAVR AV mean gradient were associated with smaller increases in LVEF (eTable 5 in the Supplement).

Table 2. Multivariable Predictors of Early LVEF Improvement (Increase of ≥10% Points) After TAVR.

Characteristic	Full model		Parsimonious model
Characteristic	OR (95% CI)	P value	OR (95% CI)	P value
Age	1.00 (0.97-1.03)	.98	NA	NA
Male	0.98 (0.53-1.83)	.96	NA	NA
BMI	1.06 (1.02-1.10)	.005	1.06 (1.02-1.10)	<.001
STS score	0.99 (0.93-1.05)	.67	NA	NA
NYHA class III/IV	1.59 (0.83-3.04)	.16	NA	NA
Hypertension	0.73 (0.37-1.42)	.35	NA	NA
Diabetes	0.55 (0.34-0.86)	.01	0.61 (0.40-0.92)	.02
Coronary artery disease	1.20 (0.69-2.07)	.52	NA	NA
Prior MI	0.64 (0.40-1.04)	.07	0.65 (0.42-0.98)	.04
Prior PCI	1.49 (0.93-2.36)	.09	NA	NA
Prior CABG	0.76 (0.46-1.24)	.27	NA	NA
Prior BAV	0.57 (0.31-1.05)	.07	NA	NA
Cerebrovascular disease	1.08 (0.54-2.18)	.83	NA	NA
Peripheral artery disease	0.78 (0.49-1.24)	.30	NA	NA
Chronic kidney disease^a	0.80 (0.43-1.49)	.48	NA	NA
COPD	1.22 (0.77-1.94)	.41	NA	NA
Oxygen-dependent lung disease	2.03 (0.69-5.98)	.20	NA	NA
Cancer	0.50 (0.32-0.80)	.003	0.56 (0.37-0.86)	.008
Hemoglobin, g/dL	0.97 (0.86-1.09)	.63	NA	NA
Baseline LVEF, %	0.93 (0.90-0.96)	<.001	0.93 (0.90-0.95)	<.001
LV mass index, g/m²	1.00 (1.00-1.01)	.72	NA	NA
LVEDD, cm	0.61 (0.43-0.87)	.006	0.59 (0.44-0.78)	<.001
AV area, cm²	0.16 (0.03-0.78)	.02	0.19 (0.05-0.73)	.02
LVOT Doppler stroke volume index	1.02 (0.99-1.06)	.20	1.03 (1.00-1.06)	.04
≥Moderate AR	0.96 (0.49-1.86)	.90	NA	NA
≥Moderate MR	0.80 (0.50-1.28)	.34	NA	NA
Discharge medication
β-Blocker	0.96 (0.60-1.54)	.87	NA	NA
ACE inhibitor/ARB	1.05 (0.70-1.58)	.81	NA	NA
Procedural complications (≤7 d)	1.18 (0.69-2.00)	.55	NA	NA
Post-TAVR AV mean gradient	1.05 (0.98-1.11)	.15	NA	NA
Severe prosthesis-patient mismatch	0.52 (0.27-1.01)	.054	0.59 (0.32-1.07)	.08
Valve type (SAPIEN 3 vs SAPIEN/SAPIEN XT)	0.66 (0.41-1.08)	.10	NA	NA
Valve size	0.94 (0.83-1.07)	.37	0.91 (0.83-1.01)	.07

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Abbreviations: ACE, angiotensin-converting enzyme; AR, aortic regurgitation; ARB, angiotensin II receptor blocker; AV, aortic valve; BAV, balloon aortic valvuloplasty; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; MI, myocardial infarction; MR, mitral regurgitation; NA, not applicable; NYHA, New York Heart Association; OR, odds ratio; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons; TAVR, transcatheter aortic valve replacement.

SI conversion factors: To convert creatinine to micromoles per liter, multiply by 88.4; hemoglobin to grams per liter, multiply by 10.

^{^a}

Serum creatinine >2 mg/dL.

Association Between LVEF Improvement and 5-Year Outcomes

The Kaplan-Meier rate of the primary end point of 5-year all-cause death was 55.6% in the overall study cohort. In univariate analysis, patients with vs without early LVEF improvement had lower rates of 5-year all-cause death (102 [50.0%; 95% CI, 43.3-57.1] vs 246 [58.4%; 95% CI, 53.6-63.2]; P = .04) and cardiac death (52 [29.5%; 95% CI, 23.2-37.1] vs 135 [38.1%; 95% CI, 33.1-43.6]; P = .05) but similar rates of noncardiac death (38 [22.4%; 95% CI, 16.7-29.7] vs 292 [27.6%; 95% CI, 22.9-33.0]; P = .21) and rehospitalization (85 [44.2%; 95% CI, 37.3-51.8] vs 184 [47.3%; 95% CI, 42.2-52.8]; P = .52) (Figure). There were no significant differences in the rates of the composite of all-cause death or rehospitalization (133 [63.5%; 95% CI, 57.0-70.1] vs 300 [70.3%; 95% CI, 65.8-74.7]; P = .18), cardiac death or rehospitalization (114 [56.7%; 95% CI, 49.8-63.8] vs 216 [59.7%; 95% CI, 54.7-64.8]; P = .62), NYHA functional class III/IV (6 of 76 [7.9%; 95% CI, 3.0-16.4] vs 16 of 119 [13.4%; 95% CI, 7.9-20.9]; P = .26), and mean (SD) Kansas City Cardiomyopathy Questionnaire Overall Summary Score (75.6 [19.6] vs 73.9 [21.8]; P = .58) at 5 years between the 2 groups (eFigures 2-4 in the Supplement).

Figure. — Time to event curves of 5-year all-cause death (A), cardiac death (B), noncardiac death (C), and rehospitalization (D) in patients with vs without LVEF improvement (defined as an increase of ≥10% points over baseline LVEF at 30 days) after transcatheter aortic valve replacement.

In multivariable analyses, early improvement in LVEF (modeled as a continuous variable) was associated with lower 5-year all-cause death (adjusted hazard ratio per 5% increase in LVEF, 0.94 [95% CI, 0.88-1.00]; P = .04) and cardiac death (adjusted hazard ratio per 5% increase in LVEF, 0.90 [95% CI, 0.82-0.98]; P = .02) after TAVR (Table 3). Restricted cubic spline analysis demonstrated a visual inflection point at ΔLVEF of 10% beyond which there was a steep decline in all-cause mortality with increasing degree of LVEF improvement (eFigure 5 in the Supplement). When modeled as a dichotomous variable, early LVEF improvement of 10% points or more was associated with lower 5-year all-cause death and cardiac death; however, this difference did not reach statistical significance (all-cause death vs cardiac death: adjusted hazard ratio, 0.79 [95% CI, 0.62-1.02]; P = .06 vs 0.75 [95% CI, 0.53-1.05]; P = .09).

Table 3. Adjusted Association Between Early LVEF Improvement and 5-Year Clinical Outcomes After Transcatheter Aortic Valve Replacement^a.

Outcome	LVEF improvement (per 5% increase)		Increase in LVEF ≥10% points
Outcome	aHR (95% CI)	P value	aHR (95% CI)	P value
All-cause death	0.94 (0.88-1.00)	.04	0.79 (0.62-1.02)	.06
Cardiac death	0.90 (0.82-0.98)	.02	0.75 (0.53-1.05)	.09
Noncardiac death	0.97 (0.87-1.07)	.51	0.82 (0.54-1.22)	.32
Rehospitalization	0.98 (0.92-1.06)	.64	0.93 (0.70-1.22)	.59
Death or rehospitalization	0.97 (0.92-1.03)	.31	0.88 (0.70-1.09)	.24
Cardiac death or rehospitalization	0.99 (0.93-1.05)	.66	0.97 (0.76-1.24)	.82

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Abbreviations: aHR, adjusted hazard ratio; LVEF, left ventricular ejection fraction.

^{^a}

Multivariable models adjusted for the following covariates: sex, body mass index, Society of Thoracic Surgeons score, diabetes, prior myocardial infarction, cancer, and baseline LVEF.

In secondary analyses, LVEF improvement at 1 year was associated with significantly lower 5-year all-cause death, cardiac death, all-cause death or rehospitalization, and cardiac death or rehospitalization (eTable 6 and eFigure 6 in the Supplement).

The association between early LVEF improvement and outcomes was consistent regardless of the presence or absence of CAD or prior MI (Table 4). Subgroup analyses demonstrated a significant interaction by sex such that early LVEF improvement was associated with lower 5-year all-cause death, cardiac death, all-cause death or rehospitalization, and cardiac death or rehospitalization in female individuals but not in male individuals (Table 4; eTable 7 and eFigure 7 in the Supplement).

Table 4. Association Between Early LVEF Improvement and 5-Year All-Cause Death After Transcatheter Aortic Valve Replacement in Prespecified Subgroups.

Subgroup	LVEF improvement (per 5% increase)			Increase in LVEF ≥10% points
	aHR (95% CI)	P value		aHR (95% CI)	P value
	aHR (95% CI)	Effect	Interaction	aHR (95% CI)	Effect	Interaction
Age, y
<80	0.89 (0.79-1.00)	.06	.26	0.6 (0.38-1.03)	.06	.30
≥80	0.96 (0.90-1.03)	.27	.26	0.8 (0.65-1.09)	.19	.30
Sex
Male	1.01 (0.94-1.08)	.88	.01	1.0 (0.80-1.37)	.73	.004
Female	0.84 (0.75-0.95)	.005	.01	0.5 (0.31-0.75)	.001	.004
Coronary artery disease
No	0.98 (0.86-1.11)	.71	.60	1.05 (0.65-1.69)	.83	.17
Yes	0.94 (0.88-1.00)	.06	.60	0.72 (0.55-0.94)	.02	.17
Prior myocardial infarction
No	0.96 (0.89-1.03)	.23	.68	0.83 (0.64-1.09)	.18	.57
Yes	0.93 (0.83-1.04)	.22	.68	0.71 (0.44-1.14)	.16	.57
STS score
<4	1.06 (0.74-1.50)	.76	.20	1.1 (0.31-3.60)	.93	.17
4-8	0.95 (0.86-1.05)	.29		0.9 (0.59-1.27)	.47
>8	0.89 (0.82-0.96)	.002		0.6 (0.42-0.76)	<.001
Baseline LVEF, %
≤35	0.96 (0.88-1.05)	.37	.56	0.9 (0.61-1.22)	.39	.44
>35	0.92 (0.85-1.00)	.06	.56	0.7 (0.52-0.98)	.04	.44
Baseline AVA, cm²
<0.6	0.97 (0.89-1.05)	.43	.49	0.7 (0.47-0.96)	.03	.26
≥0.6	0.93 (0.85-1.01)	.09	.49	0.9 (0.65-1.22)	.47	.26
Baseline AV mean gradient, mm Hg
<50	0.94 (0.82-1.09)	.41	.85	0.8 (0.64-1.07)	.15	.82
≥50	0.96 (0.90-1.03)	.22	.85	0.8 (0.45-1.30)	.32	.82
Baseline AR
None/mild	1.05 (0.87-1.25)	.63	.28	0.8 (0.60-0.98)	.01	.17
≥Moderate	0.94 (0.88-1.01)	.07	.28	1.3 (0.64-2.62)	.47	.17
Baseline MR
None/mild	0.92 (0.82-1.03)	.14	.40	0.8 (0.63-1.10)	.20	.53
≥Moderate	0.97 (0.90-1.05)	.46	.40	0.7 (0.45-1.11)	.13	.53

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Abbreviations: aHR, adjusted hazard ratio; AR, aortic regurgitation; AV, aortic valve; AVA, aortic valve area; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; STS, Society of Thoracic Surgeons.

Discussion

In this study of high- or intermediate-risk patients with symptomatic severe AS and baseline LVEF less than 50% undergoing TAVR, we report the following findings: (1) 1 in 3 patients experienced early improvement in LVEF of 10% points or more; (2) prior MI, diabetes, cancer, higher baseline LVEF, larger LVEDD, and larger AVA were associated with lower likelihood of early LVEF improvement, whereas higher BMI and higher SVi were associated with increased odds of early LVEF improvement after TAVR; (3) LVEF improvement at 30 days or 1 year after TAVR was associated with lower 5-year all-cause and cardiac death; and (4) there was significant interaction by sex such that early LVEF improvement was associated with improved 5-year outcomes in female individuals but not in male individuals.

Approximately 20% to 30% of patients with severe AS have LVEF less than 50%.^7,12 LV systolic dysfunction in patients with AS may be caused by afterload mismatch when LV pressure overload results in decrease in stroke volume and ejection fraction, decreased contractility due to myocyte loss and myocardial fibrosis as a result of LV hypertrophy or superimposed myocardial ischemia/infarction, or an underlying myocardial process that leads to decline in LVEF even before AS becomes severe.^12,13,14 Prior studies have shown that in extreme-/high-risk patients with symptomatic severe AS and LVEF less than 50%, approximately 50% to 60% experience early LVEF improvement (increase of ≥10% points within 30 days) after TAVR.^2,3,4 However, in the current study early improvement in LVEF was seen in only 33% of patients, likely due to the relatively higher baseline LVEF, especially in the intermediate-risk patient cohort.

Prior MI, diabetes, and cancer—comorbidities that are known to adversely influence LV systolic function either directly or indirectly (eg, cardiotoxic chemotherapy in patients with cancer) independent of severe AS—were associated with lower likelihood of LVEF improvement following TAVR. Higher baseline LVEF, larger LVEDD (a marker of LV dilation), and larger AVA (suggestive of less severe AS, and likely non-AS–related cardiomyopathy) were also associated with lower likelihood of LVEF improvement. In contrast, higher BMI and higher SVi were associated with higher odds of LVEF improvement after TAVR. Patients with severe AS and reduced SVi (or low flow) tend to have lower LVEF and greater myocardial fibrosis, which could explain the positive association between SVi and LVEF recovery following TAVR.^15,16 The mechanism underlying the association of higher BMI with LVEF improvement is unclear but may play in role in the obesity paradox (lower 1-year mortality in patients with overweight and obesity compared with patients with normal weight) seen after TAVR.¹⁷ The independent predictors of early LVEF improvement identified in this study may help counsel patients about the expected benefits of TAVR in terms of LVEF recovery and to individualize treatment decisions. For instance, patients with severe AS with prior MI, diabetes, or cancer, and baseline LV dysfunction may require further optimization of guideline-directed medical therapy for heart failure with reduced ejection fraction even after TAVR.^18,19 Future studies are needed to determine if earlier intervention (eg, TAVR for moderate AS) with or without additional imaging (eg, cardiac magnetic resonance to identify different patterns of myocardial fibrosis/late gadolinium enhancement) is warranted in this patient population to improve the likelihood of LVEF recovery and clinical outcomes post-TAVR.^20,21,22

Data on the association between baseline LV dysfunction and outcomes in patients with severe AS undergoing TAVR have been inconsistent.^2,7,8 However, in patients with severe AS and LV systolic dysfunction, failure to improve LVEF after TAVR is associated with increased 1-year mortality. Similarly, incomplete LV recovery is independently associated with increased mortality and heart failure after surgical aortic valve replacement in patients with LV systolic dysfunction.²³ Our current study extends these observations to 5-year clinical outcomes by demonstrating that LVEF improvement at 30 days or 1 year after TAVR was associated with reduced all-cause and cardiac death at 5 years. Each improvement of 5% points in LVEF at 30 days was associated with a 6% and 10% lower risk of all-cause and cardiac death at 5 years, respectively. Restricted cubic spline analysis demonstrated a visual inflection point at ΔLVEF of 10% beyond which there was a steep decline in all-cause mortality with increasing degree of early LVEF improvement. We found no statistically significant differences in rehospitalization, NYHA functional class, or Kansas City Cardiomyopathy Questionnaire Overall Summary Score in patients with vs without early LVEF improvement. Thus, the pathophysiologic mechanism mediating reduced mortality in patients with LVEF recovery likely extends beyond improvement in heart failure symptoms (eg, improvement in kidney function, reduction in sudden cardiac death) and warrants further investigation.²⁴

We found that early LVEF improvement after TAVR was associated with lower all-cause and cardiac death in female individuals but not in male individuals. Several studies have demonstrated sex differences in LV remodeling in response to AS with more concentric LV hypertrophy, lower LV mass index, smaller LV cavity dimensions, smaller end-systolic and diastolic volumes, and less myocardial fibrosis in female vs male individuals.^25,26,27,28 Maladpative LV remodeling is associated with impaired survival in female individuals but not male individuals after surgical aortic valve replacement.²⁹ However, data on sex differences in reversal of LV remodeling following aortic valve replacement are conflicting. Petrov et al³⁰ reported more frequent reversal of LV hypertrophy in female vs male individuals after surgical aortic valve replacement for severe AS. Similarly, Chen et al³¹ found that female individuals with AS had favorable reverse LV remodeling with greater and earlier LV mass regression post-TAVR compared with male individuals. In contrast, other studies in patients undergoing TAVR have shown similar regression of hypertrophy as measured by LV mass index in female and male individuals.^32,33 Why LVEF improvement is associated with lower mortality in female individuals but not in male individuals remains unclear and warrants further scrutiny. Because LVEF underestimates the degree of LV systolic dysfunction in presence of concentric hypertrophy, which is more prevalent and more pronounced in female vs male individuals, it is possible that post-TAVR, the regression of the concentric hypertrophy may, at least in part, mask the magnitude of improvement in LV systolic function and LVEF such that an improvement of 10% points in LVEF in female individuals may actually represent a more important true improvement in LV systolic function than the same improvement of 10% points in male individuals. Another potential explanation is that female individuals enrolled in the PARTNER trials and registries had less comorbidities (eg, lower prevalence of CAD) and hence fewer competing risks compared with male individuals, and were therefore more likely to translate improvement in LVEF post-TAVR into mortality benefit. Nonetheless, our findings suggest that the favorable survival in female vs male individuals after TAVR demonstrated in previous studies may at least partly be mediated via improvement in LVEF.³⁴

Limitations

Our study has certain limitations that must be acknowledged. First, patients with very severe LV dysfunction (LVEF <20%) and those with low-gradient AS (AV mean gradient <40 mm Hg) were excluded from the PARTNER trials. Therefore, our findings may not be applicable to those 2 groups of patients. Second, the exact etiology of LV dysfunction was not known. Patients with LV dysfunction secondary to nonvalvular heart disease (eg, CAD, amyloidosis) may not experience LVEF recovery even after treatment of AS with TAVR. Third, our study only included patients at high or intermediate risk for surgery, so these observations may not be generalizable to low-risk patients. Lastly, these findings may not be generalizable to patients with severe AS and LV dysfunction treated with TAVR bioprostheses other than SAPIEN, SAPIEN XT, or SAPIEN 3 (Edwards).

Conclusions

In high- or intermediate-risk patients with symptomatic severe AS and LVEF less than 50% undergoing transfemoral TAVR, 1 in 3 experienced early improvement in LVEF. Prior MI, diabetes, cancer, higher baseline LVEF, larger LVEDD, and larger AVA were associated with lower likelihood of early LVEF improvement, whereas higher BMI and higher SVi were associated with increased likelihood of early LVEF improvement after TAVR. Early LVEF improvement after TAVR was associated with lower 5-year all-cause death and cardiac death. Further studies are needed to understand the pathophysiologic mechanism(s) mediating reduced mortality in patients with early LVEF recovery after TAVR.

Supplement.

eFigure 1. Early LVEF Improvement After TAVR in Patients With Severe AS and Baseline LVEF <50%

eFigure 2. Composite of All-Cause Death or Rehospitalization and Cardiac Death or Rehospitalization at 5 Years in Patients With vs. Without Early LVEF Improvement After TAVR

eFigure 3. NYHA Functional Class in Patients With vs. Without Early LVEF Improvement After TAVR

eFigure 4. KCCQ-OS in Patients With vs. Without Early LVEF Improvement After TAVR

eFigure 5. Association Between ΔLVEF and 5-Year All-Cause Mortality After TAVR

eFigure 6. 5-Year Clinical Outcomes in Patients With vs. Without LVEF Improvement at 1 Year After TAVR

eFigure 7. 5-Year Outcomes in Men and Women With vs. Without Early LVEF Improvement After TAVR

eTable 1. Baseline Characteristics of Men With vs. Without Early LVEF Improvement Following TAVR

eTable 2. Baseline Characteristics of Women With vs. Without Early LVEF Improvement Following TAVR

eTable 3. Baseline Characteristics of Men vs. Women Without Early LVEF Improvement Following TAVR

eTable 4. Baseline Characteristics of Men vs. Women With Early LVEF Improvement Following TAVR

eTable 5. Predictors of Degree of LVEF Improvement (ΔLVEF) After TAVR

eTable 6. Adjusted Association Between LVEF Improvement at 1 Year and 5-Year Clinical Outcomes After TAVR

eTable 7. Association Between Early LVEF Improvement and 5-Year Outcomes After TAVR by Sex

Click here for additional data file.^{(1.5MB, pdf)}

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