JAMA Cardiology

JAMA Cardiol. 2017 Nov; 2(11): 1197–1206. PMCID: PMC5710363

Published online 2017 Nov 15. Prepublished online 2017 Sep 27. PMID: 28973520
doi: 10.1001/jamacardio.2017.3306: 10.1001/jamacardio.2017.3306

Longitudinal Hemodynamics of Transcatheter and Surgical Aortic Valves in the

PARTNER Trial
1
Pamela S. Douglas, MD, Martin B. Leon, MD,2 Michael J. Mack, MD,3 Lars G. Svensson, MD, PhD,4
John G. Webb, MD,5 Rebecca T. Hahn, MD,2 Philippe Pibarot, DVM, PhD,6 Neil J. Weissman, MD,7 D. Craig Miller,
MD,8 Samir Kapadia, MD,4 Howard C. Herrmann, MD,9 Susheel K. Kodali, MD,2 Raj R. Makkar, MD,10
Vinod H. Thourani, MD,11 Stamatios Lerakis, MD,11 Ashley M. Lowry, MS,4 Jeevanantham Rajeswaran, PhD,4
Matthew T. Finn, MD,2 Maria C. Alu, MS,2 Craig R. Smith, MD,2 and Eugene H. Blackstone, MD4, for the PARTNER
Trial Investigators

1
Duke University Medical Center, Durham, North Carolina
2
New York Presbyterian Hospital, Columbia University Medical Center, New York
3
Baylor Scott & White Health, Plano, Texas
4
Cleveland Clinic, Cleveland, Ohio
5
St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
6
Québec Heart and Lung Institute, Laval University, Québec City, Québec, Canada
7
MedStar Washington Hospital Center, Washington, DC
8
Stanford University, Stanford, California
9
University of Pennsylvania Health System, Philadelphia
10
Cedars-Sinai Medical Center, Los Angeles, California
11
Emory University, Atlanta, Georgia
Corresponding author.
Article Information

Group Information: The members of the PARTNER Trial Investigators appear at the end of the article.

Corresponding Author: Pamela S. Douglas, MD, Duke University Medical Center, 7022 North Pavilion, Durham, NC
27715 (pamela.douglas@duke.edu).

Accepted for Publication: August 2, 2017.

Published Online: September 27, 2017. doi:10.1001/jamacardio.2017.3306

Author Contributions: Drs Douglas and Blackstone had full access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analyses.

Study concept and design: Douglas, Svensson, Webb, Pibarot, Weissman, Kapadia, Herrmann, Thourani, Smith,
Blackstone.
Acquisition, analysis, or interpretation of data: Douglas, Leon, Mack, Webb, Hahn, Weissman, Miller, Herrmann, Kodali,
Makkar, Lerakis, Lowry, Rajeswaran, Finn, Alu, Blackstone.

Drafting of the manuscript: Douglas, Leon, Finn, Blackstone.

Critical revision of the manuscript for important intellectual content: Douglas, Mack, Svensson, Webb, Hahn, Pibarot,
Weissman, Miller, Kapadia, Herrmann, Kodali, Makkar, Thourani, Lerakis, Lowry, Rajeswaran, Finn, Alu, Smith,
Blackstone.

Statistical analysis: Leon, Makkar, Lowry, Rajeswaran, Finn, Blackstone.

Obtained funding: Douglas, Svensson, Weissman, Blackstone.

Administrative, technical, or material support: Douglas, Webb, Alu, Smith, Blackstone.

Supervision: Douglas, Webb, Weissman, Miller, Kapadia, Thourani, Lerakis, Rajeswaran, Blackstone.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Dr Douglas leads the PARTNER 1 echocardiography core laboratory. Drs Leon and
Svensson are members of the PARTNER Trial Executive Committee, and Dr Svensson has ownership interest in
Cardiosolutions and Valveexchange and receives royalties from Posthorax. Dr Hahn receives speaker honoraria from
Boston Scientific and Abbott Structural and consults with Abbott Structural. Dr Herrmann has received research fund‐
ing from Edwards Lifesciences, Medtronic, St Jude, Boston Scientific, and Abbott Vascular and is a consultant for
Edwards Lifesciences. Dr Kodali consults with Edwards Lifesciences and Medtronic and has ownership interest in
Thubrikar Aortic Valve. Dr Blackstone leads the Cleveland Clinic PARTNER Publications Office, which carries out inde‐
pendent analyses stemming from the PARTNER Trial. Dr Pibarot has a research contract with Edwards Lifesciences for
echocardiogram core laboratory analyses but does not receive any personal compensation. No other disclosures were
reported.

Funding/Support: This study was funded by Edwards Lifesciences.

Role of the Funder/Sponsor: The funder had a role in the design and conduct of the study in conjunction with the
Steering Committee and collection and management of the data. All analysis and interpretation of the data, including
preparation, review, and approval of the manuscript and decision to submit the manuscript for publication, were per‐
formed by PARTNER Publications Office investigators, with no funder involvement in study proposal or design, analy‐
ses, interpretation, or the decision to publish.

Group Information: The PARTNER Trial Investigators include the following: Barnes Jewish Hospital, St Louis, Missouri:
John M. Lasala, MD, Ralph J. Damiano Jr, MD, and Brian R. Lindman, MD, MSci; Brigham and Women’s Hospital,
Boston, Massachusetts: Frederick G. Welt, MD, R. Morton Bolman, MD, Wendy L. Gross, MD, and Justina C. Wu, MD,
PhD; Cedars-Sinai Medical Center, Los Angeles, California: Raj R. Makkar, MD, Gregory Fontana, MD, and Robert J.
Siegel, MD; Cleveland Clinic Foundation, Cleveland, Ohio: E. Murat Tuzcu, MD, Lars G. Svensson, MD, PhD, and William
J. Stewart, MD; Columbia University Medical Center, New York, New York: Martin B. Leon, MD, Craig R. Smith, MD, and
Rebecca T. Hahn, MD; Cornell University, New York, New York: S. Chiu Wong, MD, Karl Krieger, MD, and Richard B.
Devereux, MD; Emory University Hospital, Atlanta, Georgia: Peter C. Block, MD, Robert Guyton, MD, and Stamatios
Lerakis, MD; Intermountain Medical Center, Murray, Utah: Brian K. Whisenant, MD, Kent Jones, MD, and Stephen
Clayson, MD; Laval Hospital, Québec City, Québec, Canada: Josep Rodes-Cabau, MD, Daniel Doyle, MD, and Philippe
Pibarot, DVM, PhD; Herzzentrum Leipzig, Leipzig, Germany: Friedrich W. Mohr, MD, Gerhard Schuler, MD, and E.
Stotdrees, MD; Massachusetts General Hospital, Boston: Igor Palacios, MD, Gus Vlahakes, MD, and Jonathon J.
Passeri, MD; Mayo Clinic, Rochester, Minnesota: Charanjit S. Rihal, MD, Kevin L. Greason, MD, and Maurice E. Sarano,
MD; Medical City Dallas, Dallas, Texas: Todd Dewey, MD, David L. Brown, MD, and Deepika Gopal, MD; Northshore
University Health System, Evanston, Illinois: Ted E. Feldman, MD, Paul J. Pearson, MD, and Stephen Smart, MD;
Northwestern Medical Center, Chicago, Illinois: Charles J. Davidson, MD, Patrick M. McCarthy, MD, and Issam A. Mikati,
MD; Ochsner Clinic, New Orleans, Louisiana: Stephen Ramee, MD, P. Eugene Parrino, MD, and Yvonne Gilliland, MD;
Scripps Clinic, La Jolla, California: Paul Teirstein, MD, Scot Brewster, MD, and David Rubenson, MD; Stanford University
Medical Center, Palo Alto, California: D. Craig Miller, MD, Alan Yeung, MD, and David Liang, MD, PhD; St Luke’s Mid
America Heart Institute, Kansas City, Missouri: Barry Rutherford, MD, A. Michael Borkon, MD, and Michael L. Main, MD;
St Paul’s Hospital, Vancouver, British Columbia, Canada: John G. Webb, MD, Anson Cheung, MD, Bradley Munt, MD,
Robert Moss, MD, and Chris Thompson, MD; University of Virginia, Charlottesville: Irving .L. Kron, MD, and Patrick
Norton, MD; University of Miami, Miami, Florida: William O’Neill, MD, Donald Williams, MD, and Martin S. Bilsker, MD;
University of Pennsylvania, Philadelphia: Joseph Bavaria, MD, Howard C. Herrmann, MD, Martin Keane, MD, and Saif
Anwaruddin, MD; University of Washington, Seattle: Mark Riesman, MD, Edward D. Verrier, MD, and Catherine M. Otto;
and Washington Hospital Center, Washington, DC: Augusto Pichard, MD, Paul Corso, MD, and Zuyue Wang, MD.

Received 2017 Apr 21; Accepted 2017 Aug 2.

Copyright 2017 American Medical Association. All Rights Reserved.

Key Points

Question

What is the durability of transcatheter heart valves and is this similar to surgical bioprostheses?

Findings

In this analysis of data from the PARTNER Trial, population hemodynamic trends showed early favor‐
able hemodynamic changes after transcatheter aortic valve replacement implantation, with midterm sta‐
bility at a median follow-up of 3.1 (maximum, 5) years, and no significant changes in surgical aortic
valve replacement. Reintervention and severely abnormal hemodynamics on echocardiograms were in‐
frequent and not associated with excess death in patients after either transcatheter aortic valve replace‐
ment or surgical aortic valve replacement.

Meaning

There is longitudinal durability of both transcatheter and surgical aortic valve replacements, with rare
findings of adverse hemodynamics or valve deterioration.

This analysis of data from the PARTNER Trial determines the midterm hemodynamic performance of
balloon-expandable transcatheter heart valves.

Abstract

Importance
Use of transcatheter aortic valve replacement (TAVR) for severe aortic stenosis is growing rapidly.
However, to our knowledge, the durability of these prostheses is incompletely defined.

Objective

To determine the midterm hemodynamic performance of balloon-expandable transcatheter heart

valves.

Design, Setting, and Participants

In this study, we analyzed core laboratory–generated data from echocardiograms of all patients enrolled
in the Placement of Aortic Transcatheter Valves (PARTNER) 1 Trial with successful TAVR or surgical
AVR (SAVR) obtained preimplantation and at 7 days, 1 and 6 months, and 1, 2, 3, 4, and 5 years
postimplantation. Patients from continued access observational studies were included for comparison.

Interventions

Successful implantation after randomization to TAVR vs SAVR (PARTNER 1A; TAVR, n = 321;
SAVR, n = 313), TAVR vs medical treatment (PARTNER 1B; TAVR, n = 165), and continued access
(TAVR, n = 1996). Five-year echocardiogram data were available for 424 patients after TAVR and 49
after SAVR.

Main Outcomes and Measures

Death or reintervention for aortic valve structural indications, measured using aortic valve mean gradi‐
ent, effective orifice area, Doppler velocity index, and evidence of hemodynamic deterioration by rein‐
tervention, adverse hemodynamics, or transvalvular regurgitation.

Results

Of 2795 included patients, the mean (SD) age was 84.5 (7.1) years, and 1313 (47.0%) were female.
Population hemodynamic trends derived from nonlinear mixed-effects models showed small early fa‐
vorable changes in the first few months post-TAVR, with a decrease of −2.9 mm Hg in aortic valve
mean gradient, an increase of 0.028 in Doppler velocity index, and an increase of 0.09 cm2 in effective
orifice area. There was relative stability at a median follow-up of 3.1 (maximum, 5) years.
Moderate/severe transvalvular regurgitation was noted in 89 patients (3.7%) after TAVR and increased
over time. Patients with SAVR showed no significant changes. In TAVR, death/reintervention was asso‐
ciated with lower ejection fraction, stroke volume index, and aortic valve mean gradient up to 3 years,
with no association with Doppler velocity index or valve area. Reintervention occurred in 20 patients
(0.8%) after TAVR and in 1 (0.3%) after SAVR and became less frequent over time. Reintervention was
caused by structural deterioration of transcatheter heart valves in only 5 patients. Severely abnormal he‐
modynamics on echocardiograms were also infrequent and not associated with excess death or reinter‐
vention for either TAVR or SAVR.

Conclusions and Relevance

This large, core laboratory–based study of transcatheter heart valves revealed excellent durability of the
transcatheter heart valves and SAVR. Abnormal findings in individual patients, suggestive of valve
thrombosis or structural deterioration, were rare in this protocol-driven database and require further
investigation.

Trial Registration

clinicaltrials.gov Identifier: NCT00530894

Introduction

Transcatheter aortic valve replacement (TAVR) is a safe and effective treatment for severe aortic steno‐
sis. However, given the relatively recent introduction of transcatheter heart valves (THV), to our knowl‐
edge, data on their durability are sparse. Late deterioration of surgically implanted bioprosthetic valves
is well described, with the reduced need for anticoagulation compared with mechanical valves seen as
an acceptable tradeoff for potential reintervention. While this risk vs benefit equation may be especially
appealing in the elderly population currently receiving TAVRs, reports of early leaflet thickening and
possible valve thrombosis demand further investigation.

As the first and largest of the randomized TAVR trials, the Placement of Aortic Transcatheter Valves
(PARTNER) 1 Trial provides a rich, independently adjudicated data resource to address these issues.
This report will analyze these data to determine the longitudinal hemodynamic profile of the SAPIEN
THV (Edwards) and assess the incidence and consequences of any adverse changes as detected by
echocardiography. Similar analyses are also performed in patients with surgical bioprosthetic aortic
valve replacement (SAVR) in the PARTNER 1 Trial.

Methods

The PARTNER 1 Trial consisted of 3 cohorts: PARTNER 1A, or high risk, which randomized patients
to either TAVR or SAVR (TAVR, n = 348; SAVR, n = 351); 1B, or inoperable, which randomized to
either medical treatment or TAVR (n = 179); and continued access (TAVR, n = 2040). The trial proto‐
col (Supplement 1) was approved by all participating institutional review boards, and all patients pro‐
vided written informed consent (eAppendix in Supplement 2). Patients received the first-generation
SAPIEN THV device. Trial details have been previously published.

This report includes all successful TAVRs (device implantation as randomized/assigned) in all 3 groups
(n = 2482) and all successful SAVRs (n = 313) (eFigure 1 in Supplement 2). Protocol-specified
echocardiograms were obtained at baseline and postimplantation intervals of approximately 7 days, 1
and 6 months, and 1, 2, 3, 4, and 5 years. Patients without any postimplantation echocardiographic data
were excluded from hemodynamic analysis (TAVR, n = 78; SAVR, n = 21), and others were censored
at the time of aortic valve reintervention, death, or end of follow-up (Figure 1). All echocardiogram
data were analyzed by a single core laboratory following best practices for randomized trials, with
demonstrated excellent reproducibility in this data set.

Echocardiograms were analyzed according to standard practices as previously described and included
peak and mean aortic valve gradients, effective orifice area (EOA), and Doppler velocity index (DVI) to
evaluate valve systolic hemodynamics and transvalvular aortic regurgitation (AR). The relevant clinical
end points are all-cause death and aortic valve reintervention due to structural deterioration.

Statistical Analysis

Average temporal trends in postprocedure and follow-up transthoracic echocardiograms were analyzed
longitudinally, accounting for both the temporal pattern and the variability both among patients and
within each patient’s sequence of measurements. A temporal decomposition nonlinear mixed-effects
model was used to resolve a number of time phases on mean response and to estimate shaping parame‐
ters for each phase. We assumed that there was no informative censoring (ie, missing data were missing
at random). Longitudinal nonlinear regression for repeated measurements (SAS PROC NLMIXED;
SAS Institute) was used to implement the temporal decomposition model. We used bootstrap method to
estimate the SE of the estimate of the mean response at selected times. Estimates at different points
were then compared using z test.

To descriptively assess the association between echocardiogram measures and composite event (death
or reintervention), we considered average observed echocardiogram measurements stratified by pres‐
ence or absence of composite event within 6-month intervals. Because not all patients had echocardio‐
gram measurements just before an event within a given interval, for this analysis, only the last echocar‐
diogram observation was carried forward to the end of each 6-month interval. This is similar to the last
observation carried forward approach generally applied when one encounters missing longitudinal ob‐
servations in longitudinal data analyses, which assumes that the hemodynamic measurements would
have been stable during this period.

Continuous variables are summarized as mean (SD). Comparisons were made using Wilcoxon rank
sum nonparametric test. Categorical data are described using frequencies and percentages.
Comparisons were made using χ2 test or Fisher exact test when frequency was less than 5. Patient-spe‐
cific echocardiogram profiles are graphed with straight lines connecting observed contiguous echocar‐
diographic estimates (eFigure 2 in Supplement 2). Asymmetric 95% CIs of the estimated temporal
trend of longitudinal responses were obtained using bootstrap percentile method. All analyses were per‐
formed using SAS statistical software version 9.4 (SAS Institute) and R software version 3.2.3 (The R
Foundation). All P values were 2-tailed, and statistical significance was set at P < .05.

Results

Among the 2482 patients who received TAVR, 2404 patients (96.9%) had at least 1 postimplantation
aortic valve mean gradient recorded, with a total of 10 746 echocardiograms. Their mean (SD) age was
84.5 (7.2) years, and 1179 (47.5%) were female (Table 1). Comorbidities were common, and all pa‐
tients had severe aortic stenosis, with a mean (SD) aortic valve peak gradient of 71.3 (22.4) mm Hg, an
aortic valve mean gradient of 44.0 (14.3) mm Hg, and an aortic valve area of 0.65 (0.19) cm2. A total of
1277 of 2449 patients (52.1%) received a 23-mm diameter THV and 1172 (47.9%) received a 26-mm
diameter THV; the implantation technique was transapical in 1056 of 2482 patients (42.5%) and trans‐
femoral in 1426 (57.5%). Baseline characteristics were similar in the SAVR cohort (Table 1). Median
follow-up in the TAVR cohort was 3.1 years, and the mean (SD) follow-up was 2.9 (1.8) years. Overall
survival and freedom from reintervention in the TAVR cohort at 5 years was 34% by nonadjusted para‐
metric analysis. Median follow-up in SAVR was 3.2 years, and the mean (SD) follow-up was 2.9 (1.9)
years. Overall survival and freedom from reintervention in SAVR at 5 years was 37% by nonadjusted
parametric analysis.
Five-year echocardiographic data were available in 424 patients who received TAVR. Comparison of
paired, serial echocardiogram data in 399 patients showed favorable changes compared with baseline
on first postimplantation study, with slight adverse changes at 5 years (Table 2). Paired baseline and
late echocardiographic data in the 49 patients with 5-year echocardiograms in the SAVR cohort (serial
echocardiogram data in 42 patients) are shown in eTable 1 in Supplement 2.

Modeled Population Hemodynamic Trends

The overall TAVR population trend in aortic valve mean gradient revealed small changes, including a
reduction from 12.1 (95% CI, 11.6-12.5) to 9.2 (95% CI, 9.06-9.41) mm Hg (P < .001) in the first few
months postimplantation with a slight increase thereafter to 10.1 (95% CI, 9.80-10.5) mm Hg (P
< .001) at 5 years (Figure 2A) (Table 3). Similar changes were noted in EOA and DVI (Figure 2B and
C) (Tables 3). Patients with 23-mm diameter and 26-mm diameter prostheses displayed similar patterns
(albeit with higher gradients and smaller DVIs and EOAs in the smaller THVs), as did those with
transapical vs transfemoral implantation routes (Table 3). The SAVR population did not show any sig‐
nificant hemodynamic changes over time (Table 3) (eFigure 3 in Supplement 2).

To address the possible clinical significance of these hemodynamic trends in TAVR, we assessed vital
status and freedom from reintervention at each 6-month period throughout follow-up and then com‐
pared hemodynamic data from last trial echocardiogram (eFigure 4 in Supplement 2). The relationship
between the last mean gradient and event-free survival changed over time, such that mean gradients
were higher among survivors for up to 3 years of follow-up but similar in survivors and nonsurvivors
thereafter. In contrast, there was no time-varying association between either last EOA or DVI and
event-free survival. Because these findings suggested a relationship between adverse events and low-
flow/low-output states, we also compared ejection fraction and stroke volume index by event-free sur‐
vival. Ejection fraction showed the same time-varying relationship as mean gradient, while stroke vol‐
ume index was uniformly higher in event-free survivors than in those with either death or aortic valve
reintervention. The SAVR cohort was too small to perform a similar analysis.

Transvalvular Aortic Regurgitation

Eighty-nine patients (3.6%) in the TAVR cohort had moderate transvalvular AR and 6 patients (0.2%)
had severe transvalvular AR on at least 1 echocardiogram during the trial, for a total of 89 patients
(3.7%) with moderate or severe AR. Of the 6 with severe AR, 4 died (3 of noncardiovascular causes
and 1 of an unknown cause), including the 3 patients included in the abnormal hemodynamics count.
Of those with echocardiograms at postimplantation and 5 years, 16 patients had moderate or severe AR
at 5 years compared with 3 at postimplantation. No patients in the SAVR cohort had severe transvalvu‐
lar AR during follow-up (2 patients had moderate AR).

Aortic Valve Reinterventions

Twenty patients (0.8%) in the TAVR cohort and 1 (0.3%) in the SAVR cohort met the protocol defini‐
tion of aortic valve reintervention. In the TAVR group, 9 had SAVR, 8 had late valve-in-valve TAVR,
and 3 had balloon aortic valvuloplasty. While most reinterventions were performed for paravalvular
leak, 5 (25%) were performed for structural THV indications, including aortic stenosis in 1 patient,
valve thrombosis in 1 patient, and transvalvular AR in 3 patients. Ten of 20 patients (50%) showed no
appreciable or consistent hemodynamic changes, although the last available echocardiogram data in 9
of these 10 preceded the reintervention by more than a month and up to several years. Of the remaining
10, 1 showed a high initial mean gradient postimplantation that did not change, and 5 had no postim‐
plantation echocardiogram data. Only 4 (20%) showed the classic pattern of increasing gradients and
decreasing EOA and DVI consistent with prosthetic stenosis; just 1 of the patients with a structural in‐
dication for reintervention was in this group.

Hemodynamic Outliers and Transvalvular Regurgitation

Because the extreme risk in the PARTNER 1 population may have precluded reintervention even in the
presence of adverse hemodynamics, we evaluated the incidence of large changes between subsequent
echocardiograms as well as outlier values noted on any postimplantation echocardiogram. Both meth‐
ods are recommended by the Valve Academic Research Consortium 2 (VARC-2) to assess time-related
valve safety. In applying the VARC-2 criteria for mild aortic stenosis, we found that large numbers of
patients in the TAVR and SAVR cohorts met these criteria for hemodynamic outliers, from 3.5% to
49.0% of successful TAVRs and 1.6% to 45.0% of successful SAVRs, making these end points imprac‐
tical for case reviews (eTable 2 in Supplement 2). Thus, we also considered additional criteria for se‐
vere stenosis, which identified the most severely abnormal hemodynamic findings.

Using these more extreme cut points, an absolute mean gradient of 40 mm Hg or greater occurred dur‐
ing follow-up in 11 patients (0.5%) in the TAVR cohort, of whom 8 died (2 of cardiovascular causes, 3
of noncardiovascular causes, and 3 of unknown causes), and 1 had reintervention (82% death /reinter‐
vention). This is proportionally comparable with the numbers of patients in the overall cohort experi‐
encing these events. In addition to the 20 reinterventions, 1566 patients (63.1%) died, of whom 509 pa‐
tients died of cardiovascular causes, 566 of noncardiovascular causes, and 491 of unknown causes. An
absolute value of DVI of 0.25 or less occurred in 46 patients (1.9%), of whom 22 died (5 of cardiovas‐
cular causes, 5 of noncardiovascular causes, and 12 of unknown causes), and none had reintervention,
for a death/reintervention incidence of 50%. A between-echocardiogram increase in aortic valve mean
gradient of 20 mm Hg or greater occurred in 10 patients (0.5%), 6 of whom died (3 of cardiovascular
causes, 2 of noncardiovascular causes, and 1 of unknown causes), and none had reintervention, for an
event incidence of 60%.

Applying these same criteria to the 292 patients in the SAVR cohort showed that 1 (0.3%) had an abso‐
lute mean gradient of 40 mm Hg or greater and died of noncardiovascular causes, and no patient had a
between-echocardiogram increase in mean gradient of 20 mm Hg or greater. One patient had a valve-
in-valve TAVR placed. An absolute value of DVI of 0.25 or less occurred in 6 patients (0.2%), of whom
5 died (1 of cardiovascular causes, 2 of noncardiovascular causes, and 2 of unknown causes).

Discussion

This report of 2482 patients who received TAVR in the PARTNER 1 Trial is the largest, core laborato‐
ry–based study of transcatheter heart valves performed to date to our knowledge. Population modeling
of hemodynamic trends showed 2 phases in TAVR, with consistency across variables (mean gradient,
DVI, and EOA), reflecting early favorable changes in the first few months with minimal longitudinal
changes out to 5 years. Similarly, severely abnormal hemodynamic data in individual patients, which
might be suggestive of valve thrombosis or stenosis, were rare in this protocol-driven database.
However, echocardiogram data suggest a slight hemodynamic deterioration and increasing AR preva‐
lence. Nevertheless, an early signal for deterioration also noted in prior reports does not appear to be
more frequent in patients after TAVR than in patients after SAVR. Together, these data demonstrate ex‐
cellent durability of THV, comparable with surgical prostheses and consistent with reports in smaller
cohorts (including a small subset of the current patients) or those with shorter follow-up.

Because of the very large population, we were able to create statistically robust models of longitudinal
hemodynamic trends in the TAVR cohort. The early favorable changes have been reported previously in
patients after SAVRs and were also seen in this study. These changes suggest the possibility of early re‐
modeling of the valves and/or postprocedural changes in loading conditions or physiology, such as left
ventricular function. The possibility of very early valve thrombosis within days of implantation, as has
been reported, followed by short-term resolution, cannot be excluded given our data’s limited temporal
resolution. The observation of relative stability to 5 years is reassuring. Nonetheless, further evaluation
for a longer follow-up period is warranted, as most reports suggest that bioprosthetic dysfunction is
minimal until 8 to 10 years after implantation.

An important word of caution arises from the Valve-in-Valve International Data Registry, which report‐
ed a time to intervention for bioprosthetic valve failure of only 9 (interquartile range, 6-12) years.
Structural valve deterioration is not typically an acute process, and the development of stenosis (40% of
patients), transvalvular regurgitation (30% of patients), or both stenosis and regurgitation (30% of pa‐
tients) would presumably begin well before the need for intervention. Thus, the small but significant
changes in EOA and DVI as well as the increase in the incidence of moderate/severe transvalvular AR
between discharge and 5 years is important, albeit probably expected for any tissue bioprosthesis, and
mandates continued surveillance.

Although the patients in the SAVR cohort in the PARTNER Trial cannot be compared directly with the
pooled TAVR data because these groups were not randomized, the not-dissimilar findings are reassur‐
ing, especially given the differences between the procedures (retention of leaflets in TAVR) and the de‐
vices (presence of sewing rings in SAVR). Further, the longitudinal changes we observed are similar in
magnitude and direction to that reported in 2 of the few other core laboratory–based studies of surgical
bioprostheses, both conducted in elderly populations with a high prevalence of comorbid conditions.

Much attention has focused on recent reports of valve thrombosis and leaflet thickening, with incidence
estimates varying greatly depending on the timing and type of assessments. While this appears to occur
early after implantation, it may be associated with later leaflet degeneration and/or pannus ingrowth,
leading to structural failure. Our finding of infrequent hemodynamic deterioration is reassuring, as it
minimizes concerns regarding possible longer-term consequences of valve thrombosis. In contrast, the
increasing incidence of transvalvular regurgitation in TAVR is of concern.

Finding associations between clinical events and preceding adverse hemodynamic changes is difficult,
given the periodic nature of clinical trial surveillance assessments. Although causal hemodynamic
changes must precede an event, they may occur nearly simultaneously or at least during the same inter‐
val between assessments, making such changes difficult to discern when comparing surveillance hemo‐
dynamic data and subsequent events. To minimize this problem, we compared the last hemodynamic
measures obtained in an event-free cohort vs one with death or reintervention, finding that event-free
survival was associated with higher mean gradient and ejection fraction up to 3 years, but there was no
relationship between DVI and EOA and events at any point during follow-up. If events were caused by
valve dysfunction, mean gradients would be lower in survivors and DVI and EOA higher, relationships
which were not observed. Instead, the constant association between events and lower stroke volume in‐
dex suggests that low-flow/low-output states may be more closely associated with morbidity than ad‐
verse valve hemodynamics. The association of these distinct hemodynamic patterns with death/reinter‐
vention cannot be proven but likely reflects a primary causative role for underlying or concomitant dis‐
ease rather than valve deterioration.

Reintervention was quite rare in this TAVR cohort, became less frequent over time, and was usually not
due to structural deterioration of THV. Unfortunately, protocol-driven echocardiogram data were tem‐
porally distant and uninformative, highlighting the critical importance of real-time clinical data.
Collection of such information in future studies could aid considerably in finding associations between
hemodynamic changes and events.

Valve durability is an important and ongoing question, and consensus guidelines have been developed
to aid in its detection. To our knowledge, the current VARC-2 cut points for time-varying safety and
mild aortic stenosis have not been previously applied in a large patient cohort. We found that they were
commonly met by patients in both the TAVR and SAVR cohorts, suggesting that they may not ade‐
quately discriminate adverse changes. This is especially true for decreases in EOA noted on subsequent
echocardiograms, which were found in one-third to one-half of patients. While the known difficulty in
accurately measuring left ventricular outflow track diameter (required for calculation of valve area us‐
ing the continuity equation) may introduce substantial variability, the use of DVI, a dimensionless ratio
of the integral of flow velocities above and below the valve that avoids the need for outflow tract mea‐
surement and controls for high flow states such as regurgitation, offered only slight improvement.
While other investigators have offered varying cut points, including greater than 50% or a 10–mm Hg
increase in mean gradient, variability in echocardiogram data may be hard to distinguish from true he‐
modynamic changes; either or both can arise from physiologic changes (eg, anemia or reduced ventric‐
ular function), deficiencies in image acquisition, and/or inaccurate analysis (which should have been
minimized in this core laboratory–based study with excellent reproducibility). Future proposed parame‐
ters assessing valvular dysfunction should be tested empirically in the PARTNER Trial or other large
data sets to ensure that they provide the desired discrimination.

The VARC-2 criteria for severe stenosis were rarely met by patients in either the TAVR or SAVR co‐
horts and were not associated with an excess incidence of death or reintervention compared with the
overall trial results. Importantly, these criteria were designed to detect mild AS (from any cause) during
postimplantation surveillance and not to define early structural valve deterioration. In this respect, large
changes in hemodynamics between echocardiograms were infrequent and of unclear clinical signifi‐
cance. Whether this is caused by inherent variability in echocardiogram findings, the temporal distance
of adverse hemodynamics from clinical events, absent hemodynamic changes in patients with valve
dysfunction (as has been reported with valve thrombosis), or some other reason, our findings suggest
that annual surveillance echocardiography after TAVR may not always provide the expected early
warning for valve deterioration in the first 5 years after implantation.

Limitations

The PARTNER 1 Trial represents a unique and carefully curated large data set, which, despite low
event-free survival (34% at 5 years), yielded a robust patient cohort at 5 years, representing the entire
trial rather than a substudy population. Nevertheless, this is a small proportion of those enrolled, large‐
ly owing to high mortality in this aged cohort. Although survivorship bias may have affected our re‐
sults, with some deaths perhaps due to undetected valve deterioration, the lack of adverse population
trends in valve hemodynamics or excess events in those individuals with outlier echocardiogram find‐
ings mitigates these concerns. As TAVR use broadens to younger and less comorbid populations, long-
term durability becomes increasingly important. To this end, the timely collection and reporting of data
establishing long-term durability beyond the 5 years reported in this article is still needed.

As noted above, the protocol-mandated surveillance echocardiograms were performed only at infre‐
quent times that were not necessarily related to clinical events. While not ideal, this would be true in
any prospective study design and can be mitigated by rigorous clinical data collected at the time of ad‐
verse events. The hemodynamic trend data were extrapolated from the actual dates of echocardiogram
performance, which varied by patient regardless of the protocol-specified duration postimplantation.
Further, early changes from implantation to 3 months were modeled on population trends over this in‐
terval, as only 30-day and 6-month echocardiograms were mandated.

Although all echocardiograms were interpreted centrally with strict quality controls, our results may
still be limited by poor image quality and/or completeness, as late follow-up echocardiograms were of‐
ten obtained in the community rather than at the certified enrolling sites. The small number of patients
with hemodynamic deterioration precluded modeling of predictors or associated factors. Additionally,
paravalvular leak is a significant complication of TAVR, especially in the first generation of valves,
with significant prognostic implications. Finally, these data apply only to the first-generation SAPIEN
prostheses and not to later, more current iterations of this device or to other THV designs. In addition,
only 23-mm- and 26-mm-diameter valves were available, and device choice was made based on single-
plane linear systolic annular dimensions; thus, the effect of sizing parameters cannot be assessed accu‐
rately given the current methods of sizing the THV.

Conclusions

This large, core laboratory evaluation of 2482 patients receiving TAVR and 313 receiving SAVR in the
PARTNER 1 Trial demonstrates excellent longitudinal durability of the SAPIEN THV using both pop‐
ulation hemodynamic trends as well as case reviews of reintervention and patients with large adverse
changes between echocardiograms. Abnormal findings in individual patients suggestive of valve throm‐
bosis or structural deterioration were rare in this protocol-driven database and require further
investigation.

Notes

Supplement 1.

Trial protocol.
Supplement 2.

eAppendix. Institutional review board approval.

eFigure 1. CONSORT diagram showing patient flow.

eFigure 2. Hemodynamic data.

eFigure 3. Temporal trends in surgical aortic valve replacement.

eFigure 4. Associations between last mean gradient, Doppler velocity index (DVI), ejection fraction (EF) and stroke volume in‐
dex (SVI) by vital status/reintervention during each 6 month interval of follow-up.

eTable 1. Surgical aortic valve replacement patients with available paired echocardiographic data at baseline, first postimplanta‐
tion, and 5 years.

eTable 2. Incidence of VARC-2 and other selected cut points for severe aortic stenosis.

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Figures and Tables

Figure 1.

STROBE Flowchart Showing Patient Flow

SAVR indicates surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.

a
SD: 45 days.
Table 1.

Transcatheter Aortic Valve Replacement (TAVR) and Surgical Aortic Valve Replacement (SAVR) Population Descriptions

Characteristic TAVR Cohort, No./Total No.a SAVR Cohort, No./Total No.a

(%) (%)

PARTNER 1 cohort

Cohort A 321/2482 (12.9) 313/313 (100)

Cohort B 165/2482 (6.6) NA

Randomized continuing access cohort B 39/2482 (1.6) NA

Nonrandomized continuing access cohort A 1742/2482 (70.2) NA

Nonrandomized continuing access cohort B 215/2482 (8.7) NA

Baseline characteristics

Age, mean (SD), y 84.5 (7.15) 84.5 (6.33)

Female 1179/2480 (47.5) 134/313 (42.8)

White 2342/2479 (94.5) 294/313 (93.9)

Hypertension 2280/2479 (92.0) 294/313 (93.9)

Diabetes 917/2482 (36.9) 128/313 (40.9)

History of renal disease 448/2482 (18.0) 69/313 (22.0)

History of pulmonary disease 1550/2478 (62.6) 211/313 (67.4)

History of coronary artery disease 1928/2479 (77.8) 241/313 (77.0)

Presence of ≥1 preprocedure coronary artery stenosis 2216/2414 (91.8) 264/288 (91.7)

>50%

History of myocardial infarction 638/2467 (25.9) 90/310 (29.0)

NYHA class 3 or 4 heart failure symptoms 2354/2479 (95.0) 297/313 (94.9)

Peripheral arterial disease 1737/2482 (70.0) 210/313 (67.1)

STS risk score >10 1552/2473 (62.8) 231/313 (73.8)

Baseline echocardiogram data

LV mass, mean (SD), g 250 (76.3) 278 (86.2)

Visual ejection fraction, mean (SD), % 52.5 (12.9) 53.4 (12.4)

Doppler stroke volume index, mean (SD), mL/m2 34.9 (10.9) 34.0 (10.7)

Peak AV gradient, mean (SD), mm Hg 71.3 (22.4) 73.3 (24.1)

Mean AV gradient, mean (SD), mm Hg 44.0 (14.3) 43.4 (14.3)

AV area, mean (SD), cm2 0.65 (0.19) 0.64 (0.19)

Doppler velocity index, mean (SD), m/s 0.20 (0.06) 0.20 (0.05)

Aortic regurgitation (moderate or severe) 261/2424 (10.8) 43/302 (14.2)

Abbreviations: AV, aortic valve; LV, left ventricular; NA, not applicable; NYHA, New York Heart Association.

aPatients with data available.

Table 2.

Patients Who Received Transcatheter Aortic Valve Replacement With Available Paired Echocardiographic Data at Baseline,
First Postimplantation, and 5 Years

Measurement No.a Mean (SD) P Valueb

Preimplantation First Postimplantation 5 y

LV diameter, cm

Diastolic 309 4.55 (0.77) 4.51 (0.80) 4.36 (0.75) .02

Systolic 272 3.36 (0.94) 3.21 (0.88) 3.24 (0.85) .69

LV mass, g 309 251.0 (76.8) 247.4 (76.3) 199.7 (63.7) <.001

Ejection fraction, % 392 52.7 (12.9) 54.5 (11.5) 54.0 (10.0) .12

Stroke volume, mL 360 67.9 (19.5) 67.2 (19.8) 68.0 (20.6) .59

Stroke volume index, mL/m2 357 36.4 (10.5) 36.0 (10.5) 36.5 (11.5) .54

AV gradient, mm Hg

Peak 393 76.3 (24.4) 20.5 (8.66) 19.0 (11.2) <.001

Mean 393 47.7 (15.9) 11.0 (4.77) 10.3 (6.40) <.001

AV area, cm2 360 0.66 (0.20) 1.66 (0.50) 1.57 (0.45) .06

Doppler velocity index, m/s 370 0.20 (0.06) 0.52 (0.14) 0.50 (0.13) .27

Prosthesis-patient mismatch, No. (%), Y/N

Moderate 370 NA 115 (31.1) 109 (29.5) .54

Severe 370 NA 67 (18.1) 79 (21.4) .54

Regurgitation (moderate or severe), No. (%)

Total aortic 387 38 (9.8) 31 (8.0) 44 (11.4) .11

Paravalvular 395 NA 24 (6.1) 19 (4.8) .43

Transvalvular 395 NA 3 (0.8) 16 (4.1) .004

Abbreviations: AV, aortic valve; LV, left ventricular; NA, not applicable.

a
Patients with available data at all 3 times.
bFirst postimplantation vs 5 years. Comparisons (continuous data) were made using Wilcoxon rank sum nonparametric test.
Comparisons (categorical data) were made using χ2 test or Fisher exact test when frequency was less than 5.
Figure 2.

Temporal Trends in Transcatheter Aortic Valve Replacement

Solid lines indicate the parametric estimate of the temporal trend after procedure; dotted lines indicate 95% CIs. Filled circles in‐
dicate grouped data without regard to the repeated measurements based on time intervals, provided here as a crude verification of
the model fit. DVI indicates Doppler velocity index.
Table 3.

Hemodynamic Trends

Model Estimate (95% CI)

Mean Gradient, EOA, cm2 DVI

mm Hg

Early hemodynamic trendsa

TAVR (first postimplantation to 3 mo)

All patients (2387 mean gradient, 2361 EOA, and 2372 DVI 12.1 (11.6-12.5) to 1.63 (1.61- 0.509 (0.504-
measurements) 9.2 (9.06-9.41) 1.64) to 0.515) to
1.72 (1.69- 0.537 (0.530-
1.75) 0.545)

P valueb <.001 <.001 <.001

Transapical TAVR (1002 mean gradient, 990 EOA, and 994 DVI 11.3 (10.6-12.3) to 1.59 (1.54- 0.495 (0.478-
measurements) 8.6 (8.31-8.75) 1.61) to 0.504) to
1.72 (1.68- 0.539 (0.530-
1.76) 0.546)

P valueb <.001 <.001 <.001

Transfemoral TAVR (1385 mean gradient, 1371 EOA, and 1378 12.5 (12.0-12.9) to 1.65 (1.62- 0.516 (0.510-
DVI measurements) 9.7 (9.50-9.91) 1.67) to 0.521) to
1.71 (1.67- 0.533 (0.522-
1.77) 0.547)

P valueb <.001 .03 .005

23-mm Diameter THV (1218 mean gradient, 1203 EOA, and 1208 13.1 (12.5-14.6) to 1.50 (1.48- 0.505 (0.497-
DVI measurements) 9.8 (9.61-10.1) 1.52) to 0.511) to
1.61 (1.57- 0.543 (0.531-
1.67) 0.552)

P valueb <.001 <.001 <.001

26-mm Diameter THV (1137 mean gradient, 1126 EOA, and 1132 11.1 (10.7-11.5) to 1.76 (1.74- 0.515 (0.508-
DVI measurements) 8.6 (8.38-8.79) 1.78) to 0.523) to
1.84 (1.79- 0.533 (0.517-
1.90) 0.543)

P valueb <.001 .004 .04

SAVR (first postimplantation to 3 mo)

All patients (286 mean gradient, 282 EOA, and 284 DVI 10.3 (5.44-18.9) to 1.46 (1.40- 0.486 (0.457-
measurements) 10.8 (10.2-11.4) 1.50) to 0.498) to
1.64 (1.44- 0.486 (0.476-
1.88) 0.510)

Abbreviations: DVI, Doppler velocity index; EOA, effective orifice area; SAVR, surgical aortic valve replacement; TAVR, tran‐
scatheter aortic valve replacement; THV, transcatheter heart valve.

a
The 95% CIs in this table are not necessarily symmetric and are equivalent to 2 SEs rather than SD. The P values shown test the
difference of the mean estimates between the 2 times and indicate statistical but not necessarily clinical significance.
b
Estimates at different points were compared using z test.