Pronostico de Estenosis Aortica de Bajo Flujo Articulo

DOI: 10.1161/CIRCULATIONAHA.112.
001290
1
Predictors of Mortality and Outcomes of Therapy in Low Flow Severe Aortic
Stenosis: A PARTNER Trial Analysis
Running title: Herrmann et al.; Predictors of Outcomes in Low Flow Severe Aortic Stenosis
Howard C. Herrmann, MD
1
; Philippe Pibarot, PhD
2
; Irene Hueter, PhD
3
; Zachary M. Gertz, MD
4
;
William J. Stewart, MD
5
; Samir Kapadia, MD
5
; E. Murat Tuzcu, MD
5
; Vasilis Babaliaros, MD
6
;
Vinod Thourani, MD
6
; Wilson Y. Szeto, MD
1
; Joseph E. Bavaria, MD
1
; Susheel Kodali, MD
3
;
Rebecca T. Hahn, MD
3
; Mathew Williams, MD
3
; D. Craig Miller, MD
7
; Pamela S. Douglas, MD
8
;
Martin B. Leon, MD
3

1
University of Pennsylvania, Philadelphia, PA;
2
Quebec Heart and Lung Institute, Laval
University, Quebec, Canada;
3
Cardiovascular Research Foundation and Columbia University,
New York, NY;
4
VCU School of Medicine, Richmond, VA;
5
Cleveland Clinic, Cleveland, OH;
6
Emory University, Atlanta, GA;
7
Stanford University, Palo Alto, California;
8
Duke University,
Durham, NC

Address for Correspondence:
Howard C. Herrmann, MD
Director, Interventional Cardiology Program
Hospital of the University of Pennsylvania
9038 Gates Pavilion
3400 Spruce St
Philadelphia, PA 19104
Tel: 215-662-2180
Fax 215-349-5894
E-mail: Howard.herrmann@uphs.upenn.edu
Journal Subject Codes: Cardiovascular (CV) surgery:[35] CV surgery: aortic and vascular
disease, Treatment:[23] Catheter-based coronary and valvular interventions:other
Rebecca T. Hahn, MD
3
; Mathew Williams, MD
3
; D. Craig Miller, MD
7
; Pamela S.. Do Do Doug ug ugla la lass, s, MMMDD
8
Martin B. Leon, MD
3
11
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Copyright by American Heart Association, Inc. All rights reserved.
DOI: 10.1161/CIRCULATIONAHA.112.001290
2
Abstract:
BackgroundThe prognosis and treatment of patients with low flow (LF) severe aortic stenosis
(AS) is controversial.
Methods and ResultsThe PARTNER trial randomized patients with severe AS to medical
management (MM) vs transcatheter (TAVR) aortic valve replacement ("inoperable" cohort) and
surgery (SAVR) vs TAVR (high risk cohort). Among 971 patients with evaluable
echocardiograms (92%), LF (stroke volume index (SVI) 35 ml/m2) was observed in 530 (55%),
LF and low ejection fraction (<50%, LEF) in 225 (23%), LF, LEF, and low mean gradient (<40
mmHg, LG) in 147 (15%). Two-year mortality was significantly higher in patients with LF
compared with normal SVI (47% vs 34%, HR 1.5, 95%CI [1.25,1.89], p=0.006). In the
inoperable cohort, patients with LF had higher mortality than those with normal flow, but both
groups improved with TAVR (46% vs 76% with LF and 38% vs 53% with normal flow,
p<0.001). In the high-risk cohort, there was no difference between TAVR and SAVR. In patients
with paradoxical LF and LG (preserved EF), TAVR reduced 1-year mortality from 66% to 35%
(HR 0.38, p=0.02). LF was an independent predictor of mortality in all patient cohorts (HR
~1.5), whereas EF and gradient were not.
ConclusionsLow flow is common in severe AS and independently predicts mortality. Survival
is improved with TAVR as compared to MM and similar with TAVR and SAVR. A measure of
flow (SVI) should be included in the evaluation and therapeutic decision making of patients with
severe AS.
Clinical Trial Registration Informationclinicaltrial.gov. Identifier: NCT00530894

Key words: aortic stenosis, aortic valve replacement, transcatheter aortic valve implantation
mmHg, LG) in 147 (15%). Two-year mortality was significantly higher in patien nnts tswwwiit thh hLF LF LF
compared with normal SVI (47% vs 34%, HR 1.5, 95%CI [1.25,1.89], p=0.006). In the
nnop op oper er rab ab able le lecccoh oo or orrtt, t, ppatients with LF had higher mmmoorrt tality than thoose se s wwit it thhhnnormal flow, but both
ggrouuups p improve vedd dwwi with th thTTTAV AV AVR RR ((4 (46% 6%%vvss776%%wwwithLLFFF an nndd d 38 38 8%% % vs vss553% 3%%wwiith h no no norm rmal al a ffflo loww, w,
p< p<<0. 0. 000 00 001) 1)).. In In Intthe hehhig ig igh- h--rrissk sk coh oh ohor orrttt, ttthe he h re re ewwwas as as nooodi diff ffeeereen ence ce cebbbet ttwe we w en en enTTTAAV AVRR R an an nd ddSA SAAVR VVR. In nnppat at tie ent ns
with paradoxxic ic ical al a LLLFFF an an and ddLG LG LG(((prrres es eser er rve vv d d d EF EF EF), ), ) TTTAV AV AVR R R re r du du duce ce ced d d1- 1- 1 ye ye y ar ar ar mmmor or orta ta tali li lity tyfffro ro rom m m 66 66 6 % to 35%
3
Aortic valve replacement (AVR) is indicated for patients with severe aortic stenosis (AS)
associated with either symptoms or left ventricular (LV) dysfunction
1, 2
. Severe AS is generally
defined as an aortic valve area <1.0 cm2 and a mean transvalvular gradient of >40 mmHg.
However, many patients with symptomatic and severe AS may have lower gradients due to left
ventricular systolic dysfunction (so called low flow, low ejection fraction), high afterload and
pronounced LV concentric remodeling (paradoxical low flow, normal ejection fraction), and
due to errors or assumptions inherent in the measurement of gradient and valve area
3-7
. These
patients have a similar or worse prognosis than those with classic AS, both with and without
surgery
6-14
. However, little is known about the prognostic value of low flow independent of
gradient and ejection fraction, and its treatment.
Transcatheter aortic valve replacement (TAVR) has recently emerged as an alternative to
open surgical AVR (SAVR) in both inoperable and high-risk patients with severe AS
15-18
. In
order to better understand the implications of low flow in severe aortic stenosis, we utilized core
echocardiographic laboratory data to examine the prognostic implications of low flow (LF), low
gradient (LG), and low ejection fraction (EF) in the prospective, randomized PARTNER trial
and to examine the comparative benefits of medical management (MM), SAVR, and TAVR.

Methods
Study Population
The Placement of Aortic Transcatheter Valves (PARTNER) trial was a multi-center, randomized
clinical trial comparing TAVR with standard therapy (SAVR) in high-risk patients (cohort A)
16

and included a prespecified cohort of patients who were not considered to be suitable candidates
for surgery (inoperable, cohort B)
15
. All patients had symptoms (NYHA class II-IV) and
gradient and ejection fraction, and its treatment.
Transcatheter aortic valve replacement (TAVR) has recently emerged as an alternative to
oppen en ensssuur urgi gi gica ca c ll l AVVVRRR (SAVR) in both inoperable an an andd high-risk pati ien ee ts swwwiit ith severe AS
15-18
. In
orde deer r to better r un unnddders rstta t nd nd ndttthe he heiiimp mp pli li l cca catti ioonns ooof llowwffllowwwiiin n sseevve vere re eaaor orti ti iccc stteeno noossi sis, s, wwwe eut util ii iz zz d ed ed cooore
ec cho ho hoca ca card rdio io ogr gr grap aphhi hicc la labbborra rato tory yydddat at ataaa to to toeeexa xa xami mi mine ne n ttthe he hepprrogn gn gnos os ostti tic im im imppl plic ic icat at aiio onns nsooff f lo lo ow w fl fl floow ow (LLF LF), ), , loow ow
gradient (LG G), ), ), aaand nddlllow ow oweeje je ect ct c io io ion nnfr fr frac ac cti tt on on on(((EF EF EF) ) ) in in nttthe he hepppro rosp sp spec ec ecti ti t ve ve ve,, ra rand nd ndom om omiz iz ized ed e PPPAR AR ARTN TN TNER trial
4
severe AS. Inclusion criteria for this trial included a site-measured echocardiographic aortic
valve area of <0.8 cm2 (or indexed AVA <0.5 cm2/m2), and either a mean transvalvular
gradient >40 mmHg or a peak aortic-jet velocity >4.0 m/s (64 mmHg). Important exclusion
criteria included substantial coronary artery disease requiring revascularization, EF <20%, or
severe (4+) aortic (AR) or mitral regurgitation (MR). Patients were treated with the Edwards
SAPIEN balloon-expandable bovine pericardial heart valve system (Edwards Lifesciences). The
primary end point for the study (both cohorts) was all-cause mortality at 1 year or more, but
follow-up has continued allowing for subsequent analyses with adjudicated events
17, 18
. All
echocardiograms were analyzed in an independent core laboratory
19
. The database for the study
is maintained at the Cardiovascular Research Foundation (New York, NY), where independent
statistical analyses can be requested by investigators.
In this analysis, patients with evaluable echocardiograms were classified into 2 groups
based on baseline echocardiographic stroke volume index of <35 ml/m2 (low flow, LF) or
normal flow (NF)
2, 4
. The LF group was then further divided based on EF <50% (LF LEF) or
normal EF (LF NEF) and gradient <40 mmHg (LF LG) or >40 mmHg (LF NG) (Figure 1). In
all groups, patients were analyzed by cohort (A=high risk, B=inoperable) and treatment received
(MM, SAVR, or TAVR).
Echocardiographic Measurements
All baseline and follow-up echocardiograms were interpreted by an independent core laboratory
housed at the Duke Clinical Research Institute. Study work flow, reproducibility testing, image
acquisition and analysis, and quality assurance data have been published
19
. All chamber
parameters were measured in standard views according to the recommendations of the American
Society of Echocardiography
20
. Left ventricular volumes and EF were measured using the
s maintained at the Cardiovascular Research Foundation (New York, NY), wheere rreiiind nd ndep ep pen en ende de dennt
tatistical analyses can be requested by investigators.
IIn Inttthi hi hisssan nnal al alyysis, patients with evaluableec ec echhoocardiograms we ww re eccclla lassified into 2 groups
bbaaseeed don basel elin in nee ec echo ho h ca ca ard rd rdio io oggr grap aphi hi hicccssttrro oke vooolummmeee in nde de dex x of of o <<3335ml ml/m /m /m222(l (low ow owfflo lo ow, w, w, LLF) F) F oor r
no norm rm rmal al al fflo loww w ((N (NFFF)
2, 2, 44
. Th Th he eLF LF F ggro ro roup up upwwwas as sttthe he hen fu fu furt rt the heer di di dvi vi vide de ded ddba ba b se se s ddd on on onEEEFF <<<50 50 50%%%(L (L (LF LE LE EF) F) orr r
normal EF (L (L LFF F NE NE NEF) F) F) aaand nn gggra ra radddie eent nt nt <<<4000mm mm mmHg Hg Hg(((LF LF LF LLLG) G)) ooor r r >>>444000mm mm mHg Hg Hg(((LF LF LF NNNG) G) G) ((Fi Fi Figu gg re 1). In
5
biplane Simpsons volumetric method combining apical four-chamber and two chamber views
when possible; if image quality was inadequate, EF was estimated visually in 5 percentage point
increments. Stroke volume and cardiac output were calculated by Doppler using the velocity-
time integral of the left ventricular outflow tract and its diameter in mid-systole of the aortic
annulus in the parasternal long axis view
19, 20
.
Statistical Analysis
All of the analyses were performed with data from the intent-to-treat population, which included
all patients who underwent randomization, regardless of the treatment actually received.
However, only patients with echocardiographic data to allow classification by stroke volume
could be included in this report (971 patients, 92%). Categorical variables were compared with
the use of Fishers exact or the chi-square tests. Continuous variables are presented as means (+
SD) or median (IQR =interquartile range) for variables with a skewed distribution and compared
with the use of the Wilcoxon Rank-Sum test. Survival curves for time-to-event variables were
constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates
and were compared with the use of the log-rank test. Multivariable analysis was performed with
the Cox proportional hazards model. We examined univariate predictors of mortality for 5
baseline echocardiographic variables relating to flow (LF, LG, LEF, AR, MR). Significant
variables were then examined in pairwise analyses with each other, and in several adjusted
multivariable models in the various patient cohorts. Baseline variables entered into the
multivariate Cox regression for adjustment were those that showed a statistically significant
difference between the LF and NF groups. All statistical analyses were performed with the use of
SAS software (v 9.2).

could be included in this report (971patients, 92%). Categorical variables werecccom ommpa paare re red d dwi wi with th
he use of Fishers exact or the chi-square tests. Continuous variables are presented as means (+
SDD))) or or or mmed ed edia ia ian (I (I IQQR QR =interquartile range) for va vaarri r aaables with a skkew ee ed dddddis istribution and compared
wwith hh the useoof f th th thee Wi Wi Wilc lcox ox oxon on onRRRan ank- k- k-Su Sum mm testt. SSurv vviiv val ccuur urvvvesss fo forr tti ime me---too-ev ev ven en nt t va va ari ri iab ab ablle l s s swe weere ee
co onns nstr tr truc uc u te tedd d oon ontthhe hebbas as sis soof f al al ll l av av avai ai aila la labl bleefo fo foll ll llow ow ow-u -uppp dda data ta awwwit it ithhh th th thee us us u eee of of of KKKap apla la lan- n- n-Me Meeie ie ier eeesti ti ima ma ate tess s
and were commmpa pa pare re ed d d wi wi with th h the he heuuuseeeooof f th th t e e lo lo log- g- g ra ra rank nk nk te te t st st s. . Mu Muult lt ltiv iv ivar ar aria ia iabl bbeean an anal al alys ys ysis is iswwwas as asppper er erfo fo f rmed with
6
Results
Baseline Characteristics of Patients With Low Flow
PARTNER trial patients with evaluable echocardiograms (n=971) were classified into low
(n=530, 55%) or normal (n=441, 45%) flow, based on a calculated Doppler stroke volume index
of <35 ml/m2 or >35 ml/m2, respectively (Table 1 and Figure 1). Low gradient (<40 mmHg)
was present in 45% of patients and AVA >0.8 cm2 was present in 19% of patients. Patients with
LF were of similar age (84 years) as patients with normal flow (NF), but were more likely male
(59% compared to 47%) and had slightly higher STS risk and Logistic Euro scores. The LF
group had more co-morbid conditions, including coronary disease, prior pacemaker, a trend to
more heart failure symptoms, and higher pulmonary artery and capillary wedge pressures than
those with NF. Procedure success was similar in the 2 groups, with a slightly longer length of
stay for those with LF. Patients with LF had numerous echocardiographic differences from those
with NF, including larger LV size (both diastolic and systolic), lower EF, lower gradient, lower
calculated aortic valve areas, less AR and more MR (Table 1). At 30 days of follow-up, there
were non-significant trends to greater all-cause mortality in patients with LF as compared to NF.
For subsequent analyses, the patients with LF were further subdivided based on a left ventricular
EF <or >50% and gradient <or >40 mmHg. Low flow and LEF (mean EF =37 +9%) were
present in 225 patients (23% of the total study population) and 147 of these patients also had a
low mean transvalvular gradient (mean gradient =29 +7 mmHg, 15% of total population,
Figure 1). Paradoxical LF with normal EF was present in 304 patients (31% of the total
population) and 139 of these patients also had LG (14% of the total population). Patients with LF
and NEF had smaller LVEDV (100 ml) than those with LEF (149 ml, p<0.0001).
Mortality of Patients With LF Severe AS
more heart failure symptoms, and higher pulmonary artery and capillary wedge ppr pres es ssuuure rress s th th than an a
hose with NF. Procedure success was similar in the 2 groups, with a slightly longer length of
ttay ay yfffor or or tttho ho hose seewwit it thhh LF L . Patients with LF had numme merro ous echocardiiog oo ra aph ph phiic ic differences from those
wwith hh NF, inclu udi di ding nggllar ar rgeeer r LV LV LV sssiz ize ee(b (b (bot otthh dias ssto oolican nnd sy sy syst stoollic cc), ) llowwwer er EEEFF, lo lo owe wwer r gr gr grad ad adie iienttt, , lo lowe we wer
ca alc lc lcul ul ulat at aed edaaaor oorti ticc va vaalv lveeeaar area eas,, lles es ssss AR AR AR aaand nd ndmmmorrreeeMR MR MR ((Ta Ta Tabl bl bleee 111). ). ). AAAt t 30 30 30ddday yyssoof of fffol ol olo lo owww-up up up, th ther er re
were non-sig ig gni ni nifi fi f ca ca ant nt nt tttre re rend ndsssto to togggre re reaate te ter r al al all- l-ca ca caus us use e e mo mo mort rt tal al ait tty y yin in inpppat at atie ie ient ntssswi wi with th thLLLF F F as as ascccom om ompa pa p red to NF..
7
Using the intent-to-treat combined (inoperable and high-risk) cohorts of the PARTNER trial, all-
cause mortality at 2 years was higher in patients with LF versus NF (47.1% versus 33.7%, HR
1.58, 95% CI: 1.28, 1.95, p<0.0001, Figure 2A). There was no additional increase in mortality
when the LF patients were further divided into those with LEF vs NEF (Figure 2B) and LG vs
normal gradient (Figure 2C), although the overall mortality in all of these subgroups remained
high approximating 50% at 2 years. A sensitivity analysis revealed no difference with a cut-point
for EF of 40% (HR 1.07, p=0.647) versus an EF of 50% (HR 1.07, p=0.606).
Effect of TAVR and SAVR on Outcome in LF Severe AS
Treatment with both open surgery and TAVR in LF patients was associated with a marked
improvement in both 1-year and 2-year survival (Figure 3). Compared to MM which had a 2-
year mortality of 76%, the mortality with TAVR and SAVR ranged from 38% to 46%. The
difference between MM and TAVR in the inoperable cohort was statistically significant (RR
0.49, 95%CI [0.33, 0.72], p=0.0002, Figure 3A), while there was no significant difference
between TAVR and SAVR in the high risk group (RR 0.86, 95% CI [0.58, 1.29], p=0.47, Figure
3B). There was a small early hazard associated with SAVR in the first 30 days. After 30 days,
the mortality curves in the high risk group of patients initially diverge with a statistically
significant lower mortality for TAVR at 6 months compared with SAVR (15.6% vs 24.7%, RR
0.60, 95% CI [0.37-0.98], p=0.04) that is no longer significant at 1 year. Similar results and
trends were apparent in the LF, LEF (on-line Supplement Figure 1) and LF, LEF, LG groups of
patients . In particular for patients with LF, LEF, and LG (Figure 4), mortality at 2 years was
markedly reduced from 80.0% to 47.1% (HR 0.43, 95% CI [0.19, 0.98], p=0.04) with TAVR
versus MM in inoperable patients, and there was no difference in high risk patients between
TAVR and SAVR (42.9% versus 37.1%, HR 1.25, 95% CI [0.66, 2.36], p=0.50).
mprovement in both 1-year and 2-year survival ( r Figure 3). Compared to MM wh whhic ic chh ha ha had d daa a 22- 2-
year mortality of 76%, the mortality with TAVR and SAVR ranged from 38% to 46%. The
diiff ff fer eeren en ence ce ebbbet et eweeeen en enMMM and TAVR in the inoper er erab able cohort wasssstati ist st stiiicca cally significant (RR
00..4999,, 95%CI [0 [0 0.3 .3 .333, 000.7 .7 . 2] 2] 2], p= p= p=0. 0. 0.00 0002 02 02, FFFigggure ee 333A), wwwhille etthe heere re ewwaaasnno osi si sggnnif ific ic icaan ant t di di dff ff ffer eren en encce ce
be etw tw twee ee eenn TA TA AVR VVR aannd ndSSAV AVVR R in in inttthe he hehhhiig ighh hri ri isk sk skgggro ro oup up up(RR RR RR 0008 .8 .86, 66, 9995% 5% 5%CCCIII [0 [0 0.5558, 8, 111.2229] 9] 9],,, p= p= p=0..47 477, , Fi Fi iguuure r
3B). Therewwas as asaasssma ma mll ll l eear rrly ly lyhhaz az azar ar ad d das as sso so s ci ci c at at ated ed edwwwit it th h h SA SAAVR VR VR iiin n nth th the efi fi firs rs rst t t 30 30 30ddday ay a s. s. s AAAft ft fter er er 30 days,
8
Comparison of Effects of AVR in LF versus NF Severe AS
Patients with LF are compared to those with NF in Figure 5. In the high risk cohort, it is
apparent that the patients with LF had higher mortality than NF patients at 2 years both with
TAVR (40% vs 25%) and with SAVR (38% vs 29%) (Figure 5A). In the inoperable group of
patients, the absolute difference in mortality between MM and TAVR was greater in the LF
patients (76.2% vs 45.9%) than in the NF group (54.7% vs 38.5%), though risk reductions were
similar (Figure 5B).
Results in Patients With Paradoxical LF and Normal EF
The results of treatment on mortality in LF, NEF (mean EF =58 +5%) patients are shown in
Figure 6 and the online supplement Figure 2. Treatment with TAVR reduced mortality as
compared to MM (p <0.001). For inoperable patients, mortality was reduced from 73% with
TAVR to 43% in MM patients (HR 0.48, 95%CI [0.28, 0.80], p=0.004), and there was no
difference in high risk patients between TAVR and SAVR (39.0% vs 38.3%, HR 0.91,
95%CI[0.57, 1.45], p=0.69) (online supplemental Figure 2). For patients with LF, NEF, and LG
(Figure 6), the difference between MM and TAVR in inoperable patients was significant at 1
year (66% vs. 35%, HR 0.38, 95%CI 0.16, 0.87], p=0.02), and there was a trend to benefit at 2
years (77% vs 57%, HR 0.51, 95%CI [0.25, 1.04], p=0.06).
Multivariable Analysis
For the combined cohorts, both LF and LG were significant univariate predictors of 1-year
(online supplement Table 1) and 2-year mortality (Table 2), while baseline AR, MR, and LEF
were not significant. In a pairwise multivariable analysis of LF and LG, only LF was an
independent predictor of an increase in mortality. Adding other baseline variables into the model
resulted in the following multivariable predictors of 2 year mortality: LF (HR 1.44, p=0.0006),
Figure 6 and the online supplement Figure 2. Treatment with TAVR reduced mmmort rt rtal al lit it ty y y as as as
compared to MM (p <0.001). For inoperable patients, mortality was reduced from 73% with
TA AVR VR VR tttoo43 43 43%%% in in nMMMM patients (HR 0.48, 95%CI CI CI [000.28, 0.80], p=0 =00.004 044)), ), aand there was no
ddi diff ffer eence in hi high gh g rris sk k kpa pa ati ti tien en ents ts tsbbet et twwe weeen n TA TAVR VR VR annd nd SAV AV AVR R (3 339. 90% 0% 0%vvs 38 38 3 .3 .3%%, %, HHR RR 0. 0.91 91 91,,,
9555%C %C %CI[ I[ I[0. 0.57 57 57,, 1. 1.4455], ], ], pp==0 =0.6 .69) 9 (((on onnli li line ne ne su suupp pp pple le leme me ment nt n aaal FFig ig gur urree e 22). ). FFFoor or pppat at aie ie ent nttsswwi with th thLLLF, F, F, NNEF EF EF,, an an nd LG L
Figure 6), tthe he hedddif if ffe fe fere re enc nc nce be be betw tw t ee ee eenn nMM MM MM aaand nd ndTTTAV AV AVR RR in in i in in nop op oper er erab ab able le lepppat at aie ie ient nt ntss swa wa w s s s si si sign gn gnif if ific ic i ant at 1
9
higher STS risk score (HR 1.06, p<0.0001), and major arrhythmia (HR 1.31, p=0.0086).
In the high-risk operable cohort (A), the only univariate echocardiographic predictor of 1
year mortality was LF (HR 1.43, p=0.0287) (online supplement Table 1). At 2 years, univariate
predictors included LF and LG. In multivariable analysis, STS risk score and major arrhythmia
were predictors of 1-year mortality, and LF, STS risk score, and major arrhythmia were
predictors of 2-year mortality (Table 2).
Finally, in the inoperable cohort (B), univariate predictors of increased 1-year mortality
included LF and LEF, but LF was the only significant variable at 2 years and when analyzed
pairwise with either LG or LEF (Table 2). In multivariable analysis, the significant predictors at
both 1 and 2 years were LF, body mass index (BMI), STS risk score, new permanent pacemaker
for increased mortality, and TAVR for improved survival.
Discussion
The major findings of this study are as follows: 1. In patients with severe AS, low flow, defined
by a SVI <35 ml/m2, is associated with a significant 50% increase in 2-year all-cause mortality
as compared to patients with normal flow. 2. The impact of low flow on subsequent mortality
was independent in multivariable analysis and was a more powerful predictor of outcome than
ejection fraction or mean transvalvular gradient. 3. Patients with severe AS and low flow as well
as those with concomitant low ejection fraction and low gradient treated with TAVR had
improved survival as compared to patients treated medically. 4. In both the inoperable and high
risk cohorts of PARTNER, low flow patients had a worse prognosis than normal flow patients,
but experienced similar benefits with therapy (TAVR was better than MM for inoperable patients
and TAVR was similar to SAVR in high risk patients). 5. Patients with paradoxical low flow
(normal EF, with normal or low gradient) also had a worse prognosis, improvement with therapy
both 1 and 2years were LF, body mass index (BMI), STS risk score, newperma annnent nt n pppac ac acem em emak aker
for increased mortality, and TAVR for improved survival.
DDDiscccus u sion
Th Th he ma ma mjo j r fi fi ind nd n in in ngssooff th hhis sttu tudy dy dyaare re reaasss ffo oll lloow ows: s: 1.. IIn npppat at tie iennntss wi with th seveeereeeAAAS, S, llow owffllo lowww, ddef efiiineeed
by by byaaaSSSVI VI VI <<<333555ml ml ml/m /m /m222, iiisss as as asso so soci ci ciat at ated ed edwwwit it ithhh aaa si si sign gn gnif if ific ic ican an anttt 50 50 50%%% in in incr cr crea ea ease se seiiinnn 22- 2-ye ye year ar ar aaall ll ll c -c -cau au ause se semmmor or orta ta tali li lity ty ty
10
as compared to MM, and similar outcomes with TAVR versus SAVR. Taken together, these
findings suggest that an assessment of low flow based on SVI may be useful in the evaluation of
all patients with severe AS. In addition, surgery and transcatheter AVR should be considered in
patients with LF despite their increased mortality compared with NF patients.
Pathophysiology of low flow
Low-flow, low-gradient aortic stenosis has classically been further categorized by the ejection
fraction. Among patients with a low EF, low flow may be attributed to poor contractile function
of the left ventricle. More recently, Hachicha and colleagues described a cohort of patients with
low-flow, low-gradient aortic stenosis but with an ejection fraction of at least 50%, termed
paradoxical low flow AS
(4)
. While these patients typically have slightly lower ejection
fractions than their comparators with normal flow and normal gradients, the low flow in these
cases has been attributed to higher global LV afterload, a restrictive physiology with pronounced
LV concentric hypertrophy, and reduced LV compliance and filling
7, 21, 22
. It may also be
associated with greater subendocardial fibrosis and reduced longitudinal deformation
23
. Non-
randomized data suggest that regardless of the etiology, patients with low-flow, low-gradient
aortic stenosis have worse outcomes with and without surgery, yet may still benefit from valve
replacement compared to medical management
6, 8, 9-14
.
In our analysis of patients with severe AS and predominantly not low gradients, a low
stroke volume was an important independent predictor of mid-term all-cause mortality as
compared to patients with normal flow. Although current guidelines emphasize the importance
of ejection fraction in the evaluation of patients with AS for surgery even when asymptomatic,
our data suggest that ejection fraction may be less important after adjustment for flow. A
unifying hypothesis for these findings is that a low forward output from the left ventricle whether
paradoxical low flow AS
(4)
. While these patients typically have slightly lower r eje je ect ctio io on nn
fractions than their comparators with normal flow and normal gradients, the low flow in these
ca ase seessha ha hassbe be beeen naatt tt ttrri ribu b ted to higher global LV af ffte te terl rlooad, a restricti ive vv pphy hy hyssi siology with pronounced
LLV cconcentricchy hy hypppert rtrrroph ph phy, y, aaand nndrreeeddu ducce eddd LV VV cccom mpl pliannc nceeean an ndd d fi filll lin in ng g
7, 7, 21, 22 222
.. IIt It mmay ay yaaals ls lsoobe bee
as sso so soci ci ciat at aed edwwwiit ith hgggreea eate te err ssu sube bennd ndoc oc ocar ar ardi di dal al l fffib ib ibrrrooosis is saannd ndrred dduc uc uced ed edllon on onggi gitu tu udi di dnnnal l de defo fo f rm rm rmat at atio io on
23 33
. NNo Nonnn-
andomizedddat at ata a asu su sugg gg gges es est t th hhat at at reg eg egar ar adl dl dles sssssof of of ttthe he he et et eio io iolo lo ogy gy g ,, pa pa pati ti tien en ents ts tswwit it ith h h lo lo low- w- wfl fl flow oww,, , lo lo low- w- wgr gg adient
11
due to afterload mismatch with high impedance, impaired myocardial contractility, restrictive
physiology, or other mechanism is a more important determinant of outcome than the mechanism
for the decrease in flow. Further study may help to elucidate whether a specific SVI or change in
SV should be used to guide the timing for valve replacement.
Benefit of AVR in LF Severe AS
Several non-randomized studies have sought to elucidate the impact of a low-flow state on
surgical outcome in patients with severe aortic stenosis. Patients with low ejection fraction and
low-flow aortic stenosis have poorer outcomes, often stratified according to the hemodynamic
response to dobutamine, and whether the left ventricle exhibits contractile reserve
7, 9, 12
. Patients
with flow reserve are more likely to improve with valve replacement, while results for those
without flow reserve have varied. Previous studies are limited by various definitions for low
flow, gradient, and valve area as well as the biases associated with cohort studies. Our analysis is
the first to include randomization, and we found a significant benefit from valve replacement.
Whether this should impact the decision to intervene, suggesting that valve replacement be based
on SVI or the response of SVI to dobutamine (flow reserve) rather than EF, may require further
prospective evaluation.
The current ACC/AHA guidelines, first published in 2006, have no specific
recommendation on the indication for AVR in patients with LF, LG AS
1
. The recent ESC
guidelines state that AVR should be considered (Class IIa) in symptomatic patients with classical
low flow AS (LF, LG, and LEF) if there is evidence of flow or contractile reserve
2
. In addition,
a new recommendation (Class IIa) is included for symptomatic patients with paradoxical LF, LG
AS (preserved EF). Low flow was defined as in this study (SVI <35 ml/m2). Due to the limited
data on the natural history and outcome of surgery in these patients, the level of evidence was C
2
.
with flow reserve are more likely to improve with valve replacement, while resuult lt lts fo fo f rr r th th thos os oseee
without flow reserve have varied. Previous studies are limited by various definitions for low
fl low oww, , , ggr grad ad adie ie ient nt n, an an nddd vvalve area as well as the bias sses ee aassociated with th h coh ohhor or ort t studies. Our analysis is
hhhe fi first to incclu lude de d ran an ndo doomi mi miza za ati ti tion on, an an andd wwweffoou ounndaaasssignni niffi fica ca anttt bbeen neef efit it fffrro rommva va vallv lve errrepl pl pac ac cem mmen en nt.
Wh Wh Whet et ethe he her r th th his is isssho hooul ulld d im im mppa pact c ttthe he hedddec ec eciis isio io on nto to toiiinttter er evveenne ne, , su suugg gg gges esti ti ting ng ngttha ha hat t vvvallv lve ere re r pl pl plac ac cem em emen en nt be bebbbaas sed e
on SVI or th he e re re resp sp spon on onse seeooof SV SV SVI I to to todddob ob obut uttam am amin in neee(f (f flo lo ow wwre re r seeerv rv rve) e) e) rrat at athe he h r th th than an anEEEF, F, F, mmmay ay ayrrreq eq equi uure further
12
The data of the present study provide new evidence for these recommendations and stress the
importance of measuring and reporting SVI in patients with severe AS.
The finding that early survival is improved with TAVR versus SAVR in LF severe AS is
intriguing. Possible explanations include the less invasive nature of TAVR, detrimental effects of
cardiopulmonary bypass on patients with limited flow or contractile reserve, and larger effective
orifice area with Sapien TAVR compared to standard bioprostheses. In one non-randomized
comparison of TAVR and SAVR in patients with low EF, there did appear to be better recovery
of EF with TAVR as compared to SAVR
14
. One possible explanation for this finding may
involve the heightened afterload sensitivity of patients with LF, LG, and LEF to the effects of
patient-prosthesis mismatch
10, 24-26
. In Clavels study, the indexed AVA post-procedure was
larger with TAVR than with SAVR; however, in our study, we found no difference in the
discharge indexed AVA in LF patients.
Paradoxical LF Severe AS
The impact of paradoxical LF, LG severe AS with a normal ejection fraction has been debated.
Several studies have suggested that these patients have a poorer prognosis and improved survival
after surgery
4, 6, 7, 13, 14
. However, a substudy of the SEAS trial found that outcomes in
asymptomatic patients with LF were no worse than those with NF
27
. Treatment decisions in these
studies were not randomized and patients in J anders study were asymptomatic with less severe
AS. Nonetheless, aortic valve events occurred in almost 50% of the LF group within 5 years
27
.
Our findings confirm the high frequency and worse prognosis of symptomatic patients
with low flow severe AS and preserved ventricular function. We also demonstrate that these
patients derive significant and similar benefit with transcatheter and surgical valve replacement
and that this benefit is observed in patients with both high and low gradient. Our analysis is the
patient-prosthesis mismatch
10, 24-26
. In Clavels study, the indexed AVA post-proc occed ed durre eewa wa wasss
arger with TAVR than with SAVR; however, in our study, we found no difference in the
diisc sccha ha harrg rge ein in inde dd xeeedd d AV A A in LF patients.
PParra radoxical LF LFF SSSev veer ere e e AS AS AS
Th Th he eeim im impa pa p ct ct t oooff pa paara aado doxxxicca cal l LF LF F, LG LG LGsssev ever er eree eAAASwwwiith th haaannnor orrma ma mall ej ej ejec ec ecti tion on onffrrracct ctio ionn nha ha h ssbe be been n deeb ebat at ted dd.
Several studie ie esssha ha have ve vesssug ug ugge geest st sted ee ttthhhat at a ttthe he ese se s pppat at aie ie ient nt nsssha ha have vv aaapppoo oo oore re er r r pr pr p og og ogno no nosi si sisssan an a d d dim im impr pr prov ov o ed survivaaal
13
first to compare outcomes in this patient population in a randomized trial with centrally
adjudicated core echocardiographic laboratory measures as well as the first to demonstrate an
improvement in survival with TAVR as compared to MM. Unlike prior studies, EF was not a
differentiating factor in the prognosis of LF patients in our study, suggesting that flow, rather
than the mechanism for reduced flow, is the key prognostic factor.
Clinical Implications
It is well established that standard parameters of AS severity, including aortic valve area,
whether measured in the cardiac catheterization laboratory or with echocardiography, vary with
flow
3
. A more comprehensive evaluation of aortic stenosis severity may include the use of
valvular resistance
5, 28
, vavlulo-arterial impedance
21, 22
, or projected valve area at normal flow
25
.
While these measures add utility in a comprehensive evaluation of aortic stenosis, our findings
suggest that stroke volume index should be included in the assessment of patients with severe
AS.
Stroke volume may vary with changes in loading conditions, volume status, and other
patient factors. Yet relying on ejection fraction may be misleading, because the stroke volume
associated with a particular ejection fraction may vary from one patient to another, depending on
the ventricular size, volume status, systemic arterial resistance and compliance, and other
variables
22
. A comprehensive approach to patient assessment is warranted, and stroke volume is
a crucial piece of information to determine prognosis and inform treatment decisions. It may be
particularly important in symptomatic patients with low gradient, in whom decision making with
regard to valve replacement is more difficult.
Limitations
We analyzed low flow based on the Doppler-derived 2-dimensional LVOT diameter and
valvular resistance
5, 28
, vavlulo-arterial impedance
21, 22
, or projected valve area at at nor oo ma ma ml l l fl fl flow ow ow
2225
.
While these measures add utility in a comprehensive evaluation of aortic stenosis, our findings
uugg gg gges es esttt th th that at at ssstrok okkeeevvolume index should be includ ud udeed d in the assesssme mmnt ntt ooof f f patients with severe
AAAS..
St Stro ro oke ke kevvoooluum umeeemma mayy va va vary yywwwit it ithh cch chan an angge gessin in i llo loaad a iin ing ggco co cond nddit it i iio ons ns ns,, , vo voolu uume me essta ta t tu tu us, s, s, annd ndoooth theeer
patient factor ors. s. s. YYYet et et rrrel el lyi yi ying nggooon nnej ej ejec ec ecti ti ion on o fffra ra act ct ctiiion on onmmmay ay aybbbe mi mi misl sl sea ea eadi di ding ng n ,, , be be beca ca caus us use e eth th heeest st stro ro oke ke k volume
14
velocity-time integral. The definition of low flow is not standardized in the literature, but we
chose a definition (SVI <35 ml/m2) that has been commonly used
4, 6, 7, 13, 14, 22
and included in
the recent ESC guidelines
2
. We also performed sensitivity and specificity testing of various SVI
values for mortality and 35 ml/m2 was near optimal in receiver-operating characteristic curve
analysis. It is possible that a 3-dimensional echocardiographic or CT assessment of the outflow
tract dimensions or invasive hemodynamic assessment could lead to different values and
conclusions
5, 29, 30
. The velocity-time integral assessed by LVOT flow may also be directly
affected by the presence of aortic regurgitation and indirectly by mitral regurgitation, both of
which differed in prevalence at baseline between LF and NF subjects. Nonetheless, neither aortic
nor mitral regurgitation had independent predictive value for subsequent mortality.
Our analysis was retrospective and subject to the limitations of an observational study.
Treatment was not prospectively randomized in any of the LF subgroups and the comparisons
and conclusions should be validated in a prospective trial. Nonetheless, it is an analysis of a
large, randomized study with core laboratory echocardiographic data, and as such is the largest
available database of patients with severe AS in which to examine the impact of LF on outcome
and therapy. The findings of dobutamine stress echocardiographic evaluation performed in some
of the PARTNER trial patients with low gradient would be of interest for this study, but were not
collected prospectively and not available for this analysis. Finally, our results cannot be
extrapolated to patients with severe obstructive coronary artery disease who were not included in
the PARTNER trial.

Conclusions
Low flow, defined by the echocardiographic SVI <35 ml/m2, is a surprisingly common finding
nor mitral regurgitation had independent predictive value for subsequent mortal lit it ty. y
Our analysis was retrospective and subject to the limitations of an observational study.
Tr rea ea eatm tm tmen enttt wa wa was no no nottt pprospectively randomized innaaany nyy of the LF sub ubbgr g ou ouups ps ps and the comparisons nn
an ndd d co c nclusion ons sshhhou ould ld l bbbeeeva va vali li lida date te teddd in in naaa pro oospppectti ivvve trri riaal al. No No None neth thel eles essss, iitt is is saaann an an nal al lys ys y is is i ooofff a a
aarg rg ge, e, e, rrran ando doomi mi mze ze edd st stud uddy y ywi wth hh cor or oreee la la labo boora aato to torry ryeeech ch c oc oc ocar addi diog og ogrra raph phhic icddat at ataaa,, aan and das as sssuc uc u h h h is is is thhhelllar argggesst st
available data ta aba ba base seeooof f pa pa pati t en en nts ts swwwit it ithh hse se seve veere re reAAASSSin in nwwwhi hi hich ch c tttoooex ex exam am amin in ine th th thee e im im impa pa pact ct ooof f f LF LF LF ooon outcome
15
in patients with severe AS. It is a more powerful predictor of subsequent mortality than either
ejection fraction or mean gradient. In patients with severe AS, low flow with both low and
normal EF is associated with increased 2-year mortality as compared to normal flow patients.
Transcatheter valve replacement improves survival as compared with medical management and
provides a similar outcome compared to surgical AVR. An assessment of flow (SVI) should be
included in the evaluation and therapeutic decision making of patients with severe AS.

Acknowledgments: The authors acknowledge the assistance of Thomas C. McAndrew, MS with
the statistical analyses (Cardiovascular Research Foundation, New York, NY).

Funding Sources: The PARTNER trial was funded by Edwards Lifesciences, Inc. No additional
funding was provided for this analysis.

Conflict of Interest Disclosures: Dr. Herrmann reports institutional research funding from
Edwards Lifesciences for participation in the PARTNER trial, Consultant: St. J ude Medical,
Paieon, Equity: Microinterventional Devices; Pibarot nothing to disclose; Hueter nothing to
disclose; Gertz- nothing to disclose; Stewart nothing to disclose; Tuzcu nothing to disclose;
Babaliaros Consultant: DirectFlow Medical, Symetis, St. J ude Medical; Thourani Advisory
Board: Edwards Lifesciences, Sorin Medical, St. J ude; Szeto Edwards Lifesciences
(PARTNER Trial steering committee and clinical case; Bavaria-Institutional research funding
from Edwards Lifesciences for participation in the Partner Trial, Consultant: St. J ude Medical;
Kodali Consultant: Edwards Lifesciences, Medtronic; Scientific Advisory Board: Thubrikar
Aortic Valve, Inc.; Medical Advisory Board: Paieon Medical; TAVI Advisory Board: St. J ude
Medical; Hahn nothing to disclose; Williams Consultant: Edwards Lifesciences; Miller
Consultant: Abbott Vascular, St. J ude Medical, Medtronic; Unpaid member of PARTNER Trial
Executive Committee (Edwards Lifesciences); Douglas Institutional research support from
Edwards Lifesciences; Leon Unpaid member of the Scientific Advisory Board of Edwards
Lifesciences; has received travel reimbursement from Edwards related to activities of the
PARTNER Trial Executive Committee.
Funding Sources: The PARTNER trial was funded by Edwards Lifesciences, Inc. c. NNNo o ad addi diti tion onal
funding was provided for this analysis.
Conflict of Interest Disclosures: Dr. Herrmann rep ports institutional research funding from
Ed Ed dwa wa ward rds Li Li ife fe fescie ienc nces e ffor or pparti ici cipa p ti t on n in nthe PA PART RT RTNER R tr trial, CCon on o suult ltan ant: St. t JJ ud u e Me Medi dica c l,
PPaie eeon o , Equity y:: MMi Micr roi oont nt nter er rve ve vent nt ntio ionna nalll DDDevvvice ess; Pib bar aroot nno notth thiin ng gto toddis isccl c oose; e; HHHue uete te er nnnoth th thin ingggtto t
di diissc s lo lo lose se; Ge Gert rt rtz- z nnoot othi hng ng ngto ddi disccclo lose see;;; St Sttew wwar arttt no notth thin ingggto to oddiisccl clos osse; ; Tuz uzzcuu u no nooth thin in ng g gtto diis iscl cloooseee;
Baba bali liaros os CCon o su sult ltan a t: DDir rec ectF tFlo low Me Medi dica cal, l Sy Symeti tiss, SSt. t. JJ ud ude Me Medi dica c l; ; TTho hour urani Addvi viso sory y
Board: Edwwar ar ards ds dsLLLif if ifes es esci ci cien ence ce cesss, SSSor or rin in nMMMed ed edic ic i al al a, SSStt. t JJ ud ud udeee; SSSzze zeto to o EEEdw dwwar ar ards ds dsLLLif if ifes esci ci cien en nce ce cesss
16
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P, P, PPPic ic cha ha h rd rdAAADD, D, BBBaav avar aria iaJJ E, E HHHer rrrm rm rman aann n HC HC HC,, Ak Ak Akin in i JJJ J , J ,, AAAnd ndder er erssson n nWN WN WN,, WWa Wang ng ngDDD, , , Po Po P co co cocck ckSSSJ ... ffor orr thhe he
PAART RTNE NERR Tr ria ial In Inve vestig gat aor rs. s. TTrranscat athe hete ter r veerrsusssur urgi gica cal l ao a rt tic icvval alverrep pla lace ceme ent nt in nhi high g -
isk patients.. N N N En En Engl gl gl JJJ MMMed dd.. 22201 111; 1; 136 3664: 4:21 21 2 87 87 87-2 -2 219 1998. 8. 8
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24. Ruel M, Al-Faleh H, Kulik A, Chan KL, Mesana TG, Burwash IG. Prosthesis-patient
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25. Blais C, Burwash IG, Mundigler G, Dumesnil J G, Loho N, Rader F, Baumgartner H,
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normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-
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26. Mohty D, Dumesnil J G, Echahidi N, Mathieu P, Dagenais F, Voisine P, Pibarot P. Impact of
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27. J ander N, Minners J , Holme I, Gerdts E, Boman K, Brudi P, Chambers J B, Egstrup K,
Kesaniemi A, Malbecq W, Nienaber CA, Ray S, Rossebo A, Pedersen TR, Skjaerpe T,
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28. Cannon J D, Zile MR, Crawford FA, Carabello BA. Aortic valve resistance as an adjunct to
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29. Doddamani S, Bello R, Friedman MA, Banerjee A, Bowers J H J r, Kim B, Vennalaganti PR,
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2011;58:402-412.
24. Ruel M, Al-Faleh H, Kulik A, Chan KL, Mesana TG, Burwash IG. Prosthesi sis- s-pa pa pati tien en enttt
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2255. BBlais C, BBur urwa wa washhhIIG, G, G, MMMun un undi digl gl gler er er GGG, DDume me mesnil ll JJ G, LLoh ohooo NN, N, RRRaad der er FFF, Ba Baaum um umga garrt r ne ne ner r H, H,,
BBBeaan anlands RS RS, CCh Chaayeer r BBB, KKaadde dem mL, L, , GGGar rrcia DD, Duuurra ang nggLLLG, G, G, PPPibaaarooot P. Pr Pr Proj ojeec ecte te t d dvaaalv vve ear reeaaaat
no norm rm rmal al al fflo loww w ra rate te immp mprro rovve vess th hheeas as asse se sesss ssmme ment nt nt oooff st st sten en enos ossis i ssev ev ver er erit i y y y in in nppat at atie ie i nnntssswi wiith th thllow oww-f -f -flo loww, w, llow ow w-
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20
Table 1. Comparison of Low Flow and Normal Flow Patients
Low Flow Normal Flow P
Baseline Characteristics
N (%) 530 (55%) 441 (45%)
Age (mean+SD) 83.5+7.7 84.1+6.9 0.65
Male (%) 59.2 46/3 <0.0001
BMI (median, IQR) 26.0 (23.0, 30.4) 25.4 (22.5, 28.9) 0.006
STS score (median, IQR) 11.2 (10.0-14.0) 11.0 (9.3-13.0) 0.02
Log Euroscore (median, IQR) 29.3 (17.0-43.2) 23.0 (16.0-34.0) <0.0001
DM (%) 401 36 0.13
NYHA class IV (%) 52 46 0.07
CAD (%) 78 70 0.004
Prior CABG (%)
Prior Stroke or TIA (%)
Rheumatic Fever (%)
Prior pacemaker (%)
Procedure
Successful Implant (%)
26 mm valve (%)
Hemo. Support (CPB/IABP, %)
Conversion to open surgery (%)
Days in hospital post (mean+SD)
Hemodynamics (mean+SD)
Pa (mmHg)
PCWP (mmHg)
Aortic gradient (mmHg)
AVA (cm2)
CI (L/Min/M2)
Echocardiographic Parameters
LVEDD(cm, mean+SD)
LVESD (cm)
LVEDV( ml)
LVESV(ml)
Ejection Fraction (%)
Stroke Volume
Stroke Volume Index
Mean Aortic Gradient
Aortic Valve Area (cm2)
Baseline AR (% mod/severe)
Baseline MR (% mod/severe)
In-Hospital Events (Adjudicated)
Death (%)
CV Death (%)
Stroke/TIA (%)
Vascular complications (%)
New PPM (%)
30-Day Events (Adjudicated)
Death (%)
CV Death (%)
Stroke/TIA (%)
47
29
1
25

97
53
6
2
7.45+3.38

30.7 +11.5
22.4+9.3
40.1+15.1
0.7+0.2
1.93+0.58

4.61+0.79
3.49+0.95
126+50
69+41
49+14
57+20
26.8+5.6
40.3+14.3
0.56+0.16
8%
25%

12
7
4
12
4

13
7
4
34
26
4
15

97
44
4
2
7.07+3.71

28.1+9.6
18.9+7.4
42.8+16.7
0.6+0.2
2.23+0.75

4.36+0.75
3.01+0.87
116+44
54+32
57+11
63+21
44.3+8.0
47.4+14.2
0.74+0.19
18%
16%

8
4
4
15
3

9
5
4
<0.0001
0.29
0.002
<0.0001

0.85
0.08
0.28
1.0
0.056

0.02
0.0005
0.14
0.5
<0.0001

<0.0001
<0.0001
0.05
<0.0001
<0.0001
0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.0005

0.06
0.10
0.79
0.11
0.88

0.08
0.09
0.98
p ( )
26 mm valve (%)
Hemo. Support (CPB/IABP, %)
Conversion to open surgery (%)
Days in hospital post (mean+SD)
Hemo odyynami mics ((me mean+SD)
Paa(((mm mm mmHg Hg Hg)) )
PC PCCWWP WP ((mmHg Hg Hg)
AAAort rt tic i gradient t (m (m mmmH mHg) g) g
AAV A AAA (cm2)
CI CII (((L/ L/ L/Mi Min//M2 M2 M2)) )
Ec E ho hoca ca card rd rdio io iogr grap apphi hi hicc c Pa Pa Para ra ramme mete ers rs s
LV LV LVED ED EDD( D( D(cm cm cm, me me mean an an+++SD SD SD)))
LVESD (cm) )
53
6
2
7.45+3.38
30.7+++1111.5
22 22.4 .4++999.333
4440..1+115.1
000.7+000.222
1.993 93++000.5558
444.61 61 61+++000.79 79 79
33. 349 49 49+++00.95 95 95
44
4
2
7.07+3.71
28 28 8.1++9. 9. 9666
18 18 18.9 . ++7. 7.444
42 42 4 .8 .8++16 16 16.7 77
000.6+000.22
2. 2.23 23 3++000.775 5
444.36 36 36+++000.75 75 75
33. 301 01 01+++00. 087 87 87
0. 0. 0.08 08 08
0. 0. 0.28 28 28
11.00
0.056
0.02
0. 0.00 0005 05
0. 0. 0.14 14 14
000.5
<<0 0.00000 00111
<0 <0 <000 .000 00 00111
<0 <<.0001
21
Table 2. Univariate and Multivariable Predictors of 2-Year Mortality by Cohort

2-YEAR MORTALITY
HR Range P
*
Combined cohorts A+B
Univariate
LF 1.53 1.25, 1.88 0.0001
LG 1.25 1.02, 1.52 0.0284
LEF 1.20 0.98, 1.48 0.0769
AR 0.98 0.73, 1.33 0.9187
MR 1.25 0.99, 1.57 0.0585
Multivariable
LF 1.44 1.17, 1.78 0.0006
STS score 1.06 1.03, 1.08 <0.0001
Arrhythmia 1.31 1.07, 1.61 0.0086
Cohort A
Univariate
LF 1.53 1.25, 1.88 0.0001
LG 1.25 1.02, 1.52 0.0284
LEF 1.20 0.98, 1.48 0.7690
AR 0.98 0.73, 1.33 0.9187
MR 1.25 0.99, 1.57 0.0585
Multivariable
LF 1.43 1.08, 1.89 0.0131
STS score 1.06 1.02, 1.10 0.0011
Arrhythmia 1.32 1.01, 1.74 0.0440
Cohort B
Univariate
LF 1.56 1.15, 2.12 0.0045
LG 1.27 0.95, 1.70 0.1073
LEF 1.35 1.00, 1.84 0.0514
AR 0.93 0.62, 1.38 0.7205
MR 1.05 0.74, 1.49 0.7964
Multivariable
LF 1.54 1.12, 2.11 0.0074
BMI 0.97 0.95, 1.00 0.0332
STS 1.04 1.01, 1.07 0.0038
PACER 1.55 1.08, 2.21 0.0175
TAVR 0.55 0.41, 0.75 0.0002
*P values are based on the Cox proportional hazards model, significant values are highlighted in yellow;
abbreviations defined in the text
LF 1.53 1.25, 1.88 00.0 .0 .000 00 0 111
LG 1.25 1.02, 1.52 0..002 0 84 84
LEF 1.20 0.98, 1.48 0. 00776 7690 90 90
AR 0.98 0.73, 1.33 0.9187
MR 1.25 0.99, 1.57 0.0585
Mu Muult lt ltiv iv ivaaria ia iabl bbleee
LF LF F 1. 1.43 43 43 111.0 .0 .08, 8, 8, 1...89 89 89 000.0 .013 133111
SSTSS S score 11. 1.06 066 11. 1.02 022, 1. 1110 0. 0. 000 00 0 1111
AAr Arrh hhyt y hmia 11.3 .3 . 222 1. 1. 101 01 0 , 1.7774 000.00044 44400
Co Cooho ho hort rt rt BBB
Univ ivar a iiate te
LF 1. 1..56 56 111.1 .115, 5, 5, 2. 2. 2.12 12 12 000.0 .0 .004 00 5
LG LG 112277 0095 95 1170 70 0010 1073 73
22
Figure Legends:
Figure 1. Flow chart of patients enrolled in the PARTNER trial and then subdivided by flow,
ejection fraction, gradient, cohort inclusion, and treatment. Abbreviations: LF (low flow), NF
(normal flow), LEF (low ejection fraction), NEF (normal EF), LG (low gradient), NG (normal
gradient), A (high risk cohort), B (inoperable cohort), TAVR (transcatheter aortic valve
replacement), SAVR (surgical aortic valve replacement), MM (medical management).

Figure 2. Kaplan-Meier all-cause mortality analysis to 2 years is shown for patients with LF vs
NF (panel A), LF with LEF vs NEF (panel B), and LF with LEF and LG versus NG (panel C).
Abbreviations: low flow (LF), normal flow (NF), LEF (low ejection fraction), NEF (normal
ejection fraction), low gradient (LG), normal gradient (NG).

Figure 3. Treatment for patients with LF severe AS enrolled in PARTNER. Comparison of
TAVR and MM in cohort B is shown in panel A and comparison of TAVR and SAVR is shown
(cohort A) is shown in panel B. Abbreviations: Low flow (LF), Transcatheter aortic valve
replacement (TAVR), medical management (MM), high risk cohort (A), inoperable cohort (B).

Figure 4. Two-year mortality is shown for both trial cohorts of patients with LF with LEF and
LG (Cohort B is in panel A and Cohort A is in panel B).

Figure 5. Comparison of treatment in patients with LF versus NF severe AS in Partner high-risk
cohort A (panel A) and the inoperable cohort B (panel B). Abbreviations: low flow (LF), normal
NF (panel A), LF with LEF vs NEF (panel B), and LF with LEF and LG versus NG NG NG (pa pa pane ne nel ll C) CC)..
Abbreviations: low flow (LF), normal flow (NF), LEF (low ejection fraction), NEF (normal
ej jec ec cti ti tion on onfffra ra ract ct ctiion) n)),, lo low gradient (LG), normal grad ad adie eent (NG).
Fi Figu gu gure re re 33.. TTTre re reat atme me ment nt fffor or ppat aie ie ent nttsss wi wi witth thLLLF FF se se seve veere re re AS AS AS enr nr n ol ol olle le led din in inPPPAR AR ARTN TN NER ER ER. Co Co Comp mp mpaaaris son onnoof f
TAVR andMMMM MM in in ncccoh ohhor oo t BBB is is i sssho ho hown wn wniiinnnpa pa pane ne nell l A A A an an nd d dco co omp mp mpar ar aris sson on onooff f TA TA TAVR VR VR aand nd ndSSSAV AV AVR R is shownn
23
flow (NF), transcatheter aortic valve replacement (TAVR), medical management (MM).

Figure 6. All-cause mortality at 2 years is compared for both Partner cohorts in patients with LF,
NEF, with LG (Cohort B is shown in panel A and cohort A is shown in panel B).
PARTNER
(N=971)
Low Flow
(N=530, 55%)
Normal Flow
(N=441, 45%)
LF NEF
(N=304, 31%)
LF LEF LG
(N=147, 15%)
LF LEF
(N=225, 23%)
A (N=350)
B (N=180)
A (N=153)
B (N=72)
A (N=105)
B (N=42)
LF LEF NG
(N=78, 8%)
TAVR (N=170)
SAVR (N=180)
TAVR (N=85)
MM (N=95)
A (N=196)
B (N=108)
TAVR (N=93)
SAVR (N=103)
TAVR (N=51)
MM (N=57)
Figure 1
Low Flow
(N=530, 55%)
LF NEF
(N=304, 31%)
LLFFF LLEEF
(((NNN==222222555,, 222333%%%))
B (N=180)
AA (NNN==15333))
BBB (((NNN===777222)))
LLFF LLEEFF NNGG
SA
TTAAA
M
A (N=196)
B ((NN==100088)))
3)
3)
11)))
)))
2
-
Y
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
Time in Months
0 4 8 12 16 20 24
530 422 368 336 312 287 265
441 368 342 318 302 282 270
Number at risk
LF
NF
p=<.0001
HR: 1.58 [95% CI: 1.28, 1.95]
47.1%
33.7%
ITT - Cohorts A & B
LF (Low Flow)
NF (Normal Flow)
Figure 2A
22
-
YY
rr

DDD
ee
aa
ttt
h

(
%
)
000
00 10
00 20
30 30
40
50
60
p= p=<<.0 000 001
HR HR HR::: 1. 1 8 58 58 [[[95 955% % %CI CI C :: 11. 1.28 28,, 11. 1. 5 95 95]]]
47.1%
33.7%
2
-
Y
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
Time in Months
0 4 8 12 16 20 24
225 177 154 142 128 119 109
304 244 213 193 183 167 155
Number at risk
LF LEF
LF NEF
p=0.7002
HR: 0.95 [95% CI: 0.73, 1.23]
48.7%
46.1%
ITT - Cohorts A & B
LF LEF
LF NEF
Figure 2B
2
-
YY
rr

DD
ee
aa
tt
h

(
%
)
000
10 10 10
20 22
30 30 3
40 40 4
50
60
70
p= pp 00.7 700 0022
HR HR H : 000.95 95 95 [9 [95% 5% 5%CCCI: I: I 00 7 .733, 3, 11.2 2 .23] 3] 3]
48.7%
46.1%
2
-
Y
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
Time in Months
0 4 8 12 16 20 24
147 115 100 94 83 76 73
78 62 54 48 45 43 36
Number at risk
LF LEF LG
LF LEF NG
p=0.6325
HR: 1.10 [95% CI: 0.74, 1.65]
48.0%
50.4%
ITT - Cohorts A & B
LF LEF LG
LF LEF NG
Figure 2C
2
-
YY
rrr

D
e
a
t
h

(
%
)
000
10 10 1
20 22
30 30
40
50
60
p= p=00.6 .632 325
R HRR:: 1. 1.10 11 [[[95 95 95%%CI:: 0. 0.74 74,, 1. 1.65 65 65]]]
48.0%
50 50 5 .4 4 .4%%%
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
85 74 65 58 55 50 47 46 46
95 78 60 47 39 35 26 25 18
Number At Risk
B-TAVR
B-MM
Log Rank P <0.001
45.9%
76.2%
LF Cohort B-TAVR
LF Cohort B-MM
Figure 3A
222
---
YY
e
a
r

D
e
a
t
h
0
1100
20
30
40
00 6600 112200 118800 224400 330000 336600 442200 448800 554400 660000 66666
LLLoooggg RRRaannkk PP <<<0.0001
4
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
170 152 143 127 123 119 112 106 100
180 138 127 123 119 116 112 107 101
Number At Risk
A-TAVR
A-SAVR
Log Rank P=0.907
39.6%
37.9%
LF Cohort A-TAVR
LF Cohort A-SAVR
Figure 3B
222
--
YY
e
a
r

D
e
a
t
000
10
220
30
40
00 6600 11222000 118800 224400 3330000 3336600 442200 448800 5544000 660000 66666
LLoooggg RRRaannnkkk PPP===00..99007
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
17 15 14 12 11 9 9 9 9
25 19 13 10 10 8 5 5 5
Number At Risk
B-TAVR
B-MM
Log Rank P=0.039
47.1%
80.0%
LF, LEF and LG Cohort B-TAVR
LF, LEF and LG Cohort B-MM
Figure 4A
222
--
YY
e
a
r

D
e
a
t
h
00
1100
20
333000
40
50
00 6600 112200 118800 224400 330000 336600 442200 448800 554400 660000 666600
LLooggg Raaannnkkk PPP=000.0
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
56 50 45 39 38 37 35 32 32
49 38 36 35 35 32 29 29 27
Number At Risk
A-TAVR
A-Surgery
Log Rank P=0.596
42.9%
37.1%
LF, LEF and LG Cohort A-TAVR
LF, LEF and LG Cohort A-Surgery
Figure 4B
222
--
YY
e
a
r

D
e
a
t
h
00
1100
20
333000
40
50
00 6600 112200 118800 224400 330000 336600 442200 448800 554400 660000 666600
LLooggg Raaannnkkk PPP=000.5
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
5
10
15
20
25
30
35
40
45
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
170 152 143 127 123 119 112 106 100
180 138 127 123 119 116 112 107 101
152 139 135 125 121 117 112 111 108
145 119 110 106 102 98 97 93 90
Number At Ri sk
A-LF-TAVR
A-LF-Surgery
A-NF-TAVR
A-NF-Surgery
Log Rank P= 0.026
39.6%
37.9%
25.3%
28.8%
A-LF-TAVR
A-LF-Surgery
A-NF-TAVR
A-NF-Surgery
Figure 5A
22
-
YYY
ee
a
r

D
e
a
t
h

(
%
0
55
100
15 15 15
20
25
30
0 6 0 6 0 60 1 0 1 0 120 20 20 18 18 180 2 0 2 0 240 40 40 30 3000 3 0 3 0 60 60 60 42 42 420 4 0 4 0 480 80 80 54 54 5 0 6 0 6 0 600 00 00 66 77 0 7
LLLooog RRaaannnkkk PPP=== 00.0002266
25 2
28
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
85 74 65 58 55 50 47 46 46
95 78 60 47 39 35 26 25 18
78 67 60 59 56 53 51 49 47
66 55 49 43 39 38 32 26 25
Number At Ri sk
B-LF-TAVR
B-LF-MM
B-NF-TAVR
B-NF-MM
Log Rank P= <.001
45.9%
76.2%
38.5%
54.7%
B-LF-TAVR
B-LF-MM
B-NF-TAVR
B-NF-MM
Figure 5B
222
--
Y
e
a
r

D
e
a
t
h
00
10
20 20 20
30 30
40
50
TTiimmmee iinn DDDaayyss
0 6 0 6 0 60 1 0 1 0 120 20 20 18 18 180 2 0 2 0 240 40 40 30 30 300 3 0 3 0 360 60 60 42 42 420 4 0 4 0 480 80 80 54 54 540 6 0 6 0 600 00 00 66 66 66000
LLoogg Raannkk P= <.0001
45 4
38
54
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
23 21 19 17 15 13 11 10 10
29 22 15 10 9 9 6 5 4
Number At Risk
B-TAVR
B-MM
Log Rank P=0.047
56.5%
76.9%
LF, NEF and LG Cohort B-TAVR
LF, NEF and LG Cohort B-MM
Figure 6A
222
---
YY
e
a
r

D
e
a
t
000
10
20
333000
40
50
000 66000 11122200 118800 224400 3300000 3366000 4422000 448800 555444000 660000 666
LLLoooggg RRRaaannnkkk PPP===000
2
-
Y
e
a
r

D
e
a
t
h

(
%
)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
43 39 38 34 34 33 29 27 26
44 33 30 30 28 28 28 27 26
Number At Risk
A-TAVR
A-Surgery
Log Rank P=0.629
39.5%
40.9%
LF, NEF and LG Cohort A-TAVR
LF, NEF and LG Cohort A-Surgery
Figure 6B
222
--
YYY
e
a
r

D
e
a
t
h
00
100
20
333000
40
50
00 6600 112200 118800 224400 330000 336600 442200 448800 554400 660000 666
LLoogg RRaankkk PPP==000

Pronostico de Estenosis Aortica de Bajo Flujo Articulo

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Pronostico de Estenosis Aortica de Bajo Flujo Articulo

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DOI: 10.1161/CIRCULATIONAHA.112.

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