Prognostic Implications of Moderate Aortic Stenosis in Patients With Left Ventricular Systolic Dysfunction

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 69, NO. 19, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2017.03.023

Prognostic Implications of Moderate Aortic Stenosis in Patients With Left Ventricular Systolic Dysfunction Lennart van Gils, MD,a Marie-Annick Clavel, DVM, PHD,b E. Mara Vollema, MD,c Rebecca T. Hahn, MD,d Ernest Spitzer, MD,a Victoria Delgado, MD, PHD,c Tamim Nazif, MD,d Peter P. De Jaegere, MD, PHD,a Marcel L. Geleijnse, MD, PHD,a Ori Ben-Yehuda, MD,d Jeroen J. Bax, MD, PHD,c Martin B. Leon, MD,d Philippe Pibarot, DVM, PHD,b Nicolas M. Van Mieghem, MD, PHDa

ABSTRACT BACKGROUND Left ventricular (LV) systolic dysfunction and moderate aortic stenosis (AS) are more frequent with advancing age and often coexist. Afterload reduction is the mainstay of pharmacological treatment of heart failure (HF). Aortic valve replacement (AVR) is only formally indicated for symptomatic severe AS. OBJECTIVES This study sought to determine the clinical outcome of patients with concomitant moderate AS and LV systolic dysfunction. METHODS Echocardiographic and clinical data of patients with moderate AS and LV systolic dysfunction between 2010 and 2015 from 4 large academic institutions were retrospectively analyzed. Moderate AS was defined as aortic valve area between 1.0 and 1.5 cm2 and LV systolic dysfunction defined as LV ejection fraction <50%. The primary endpoint was a composite of all-cause death, AVR, and HF hospitalization. RESULTS A total of 305 patients (mean age 73
11 years; 75% male) were included. The majority were symptomatic at the time of index echocardiogram (New York Heart Association [NYHA] functional class II: 42%; NYHA functional class III: 28%; and NYHA functional class IV: 4%). Ischemic heart disease was present in 72% of patients. At 4-year follow-up, the primary composite endpoint occurred in 61%. The main predictors for the primary endpoint were male sex (p ¼ 0.022), NYHA functional class III or IV (p < 0.001), and peak aortic jet velocity (p < 0.001). The rate of the composite of all-cause death or HF hospitalization was 48%, rate of all-cause death was 36%, and rate of HF hospitalization was 27%. AVR occurred in 24% of patients. CONCLUSIONS Patients with concomitant moderate AS and LV systolic dysfunction are at high risk for clinical events. Further studies are needed to determine if earlier AVR in these patients might improve clinical outcome. (J Am Coll Cardiol 2017;69:2383–92) © 2017 by the American College of Cardiology Foundation.

From the aDepartment of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands; bDepartment of Cardiology, Quebec Heart and Lung Institute/Laval University, Quebec City, Quebec, Canada; cDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; and the dDepartment of Cardiology, New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York. The Department of Cardiology of the Erasmus Medical Center Rotterdam received research grants from Claret Medical, Boston Scientific, Medtronic, and Edwards Lifesciences. The Department of Cardiology of the Leiden University Medical Center received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific. Dr. Listen to this manuscript’s

Hahn has core laboratory contracts for which she receives no direct compensation; has received consulting fees from Mitralign,

audio summary by

Inc.; has received research funding from Philips Healthcare; and is a speaker for Edwards Lifesciences, GE Medical, Abbott

JACC Editor-in-Chief

Vascular, and Boston Scientific. Dr. Delgado has received speaker fees from Abbott Vascular. Dr. Nazif has received consulting fees

Dr. Valentin Fuster.

from Edwards Lifesciences. Dr. De Jaegere is a proctor for Boston Scientific. Dr. Pibarot has received research grants from Edwards Lifesciences; and has echocardiography core laboratory research contracts with Edwards Lifesciences and Medtronic. Dr. Van Mieghem has received research grants from Claret Medical, Boston Scientific, Medtronic, and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. William Stewart, MD served as the Guest Editor for this article. Manuscript received December 30, 2016; revised manuscript received March 6, 2017, accepted March 9, 2017.

2384

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

H

ABBREVIATIONS AND ACRONYMS AS = aortic stenosis

eart failure (HF) affects up to 15% of the elderly population older than age 70 years (1,2). These pa-

tients still face a grim prognosis, with 1- and

AVA = aortic valve area

T A B L E 1 Baseline Characteristics (N ¼ 305)

Demographics Age, yrs

73
11

Male

229 (75)

5-year mortality rates of approximately 20%

Body surface area, m2

and 50%, respectively (3,4). After hospital

Obesity*

99 (33)

admission for HF, the 1-year rehospitaliza-

Diabetes

116 (38)

tion or mortality rate is as high as 20% to

Hypertension

225 (74)

80% (5). Pharmacological management of

Dyslipidemia

217 (71)

echocardiography

HF includes beta-blockers and modulation

Coronary artery disease

219 (72)

HF = heart failure

of the renin-angiotensin-aldosterone system

AVAi = indexed aortic valve area

AVR = aortic valve replacement

DSE = dobutamine stress

to reduce afterload (1,2).

NYHA = New York Heart

Degenerative aortic stenosis (AS) is a com-

Association

1.96
0.24

Prior myocardial infarction

159 (52)

Prior PCI

109 (36)

Prior CABG

86 (28)

Chronic lung disease

75 (25) 155 (51)

SAVR = surgical aortic valve

mon valve disease affecting 2% to 4% of pa-

Revascularization

replacement

tients older than age 65 years (6,7); therefore,

Creatinine level, mmol/l

TAVR = transcatheter aortic

it often coexists with left ventricular (LV)

eGFR, ml/min/1.73 m2

61
20

valve replacement

systolic dysfunction. AS gradually progresses,

Ischemic cardiomyopathy

140 (48)

Vmax = peak aortic jet velocity

with an annual reduction in aortic valve area

(AVA) of w0.1 cm 2 (8,9), and may contribute to LV systolic dysfunction through afterload mismatch (10).

109
73

Smoking

63 (22)

Peripheral arterial disease

60 (20)

Prior stroke

43 (14)

NYHA functional class

Mortality with severe AS approximates 50% after

I

79 (26)

2 years of follow-up after symptoms occur or LV systolic

II

129 (42)

dysfunction is present (11). Aortic valve replacement

III

86 (28)

(AVR) is currently indicated for patients with symp-

IV

12 (4)

tomatic, severe AS (12,13), but not for moderate AS. Life expectancy in patients with moderate AS (8,14–18) may be reduced, especially in combination with coronary artery disease and LV systolic dysfunction (14). SEE PAGE 2393

Index echocardiography LVEF, %

38
9

AVA, cm2

1.24
0.16

Indexed AVA, cm2/m2

0.64
0.12

Vmax, m/s

2.5
0.4

Peak gradient, mm Hg

27
9

Mean gradient, mm Hg

15
5

The aim of the present study was to evaluate the clinical outcome of patients with moderate AS and LV systolic dysfunction in terms of death, AVR, and hospital admissions for HF.

Values are mean
SD or n (%). *Body mass index $30 kg/m2. AVA ¼ aortic valve area; CABG ¼ coronary artery bypass grafting; eGFR ¼ estimated glomerular filtration rate; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; Vmax ¼ peak aortic jet velocity.

METHODS hypertrophic or noncompaction cardiomyopathy, and The echocardiography databases from 4 academic

congenital heart disease (i.e., unicuspid or bicuspid

centers in the United States, Canada, and the

aortic valve disease determined unequivocally by

Netherlands, between January 2010 and December

transthoracic echocardiography).

2015, were screened for patients with moderate AS and

Patient demographics and clinical follow-up in-

LV systolic dysfunction. Moderate AS was defined as

formation were collected from hospital records or

AVA >1.0 and <1.5 cm2 and peak aortic jet velocity

requested from treating physicians and referring

(Vmax) >2 and <4 m/s at rest or after dobutamine

centers. Survival status was obtained from the

stress echocardiography (DSE). LV systolic dysfunc-

respective National Population Registries whenever

tion was defined by a left ventricular ejection fraction

possible. In the United States, survival status was

(LVEF) <50%. The AVA was calculated using the con-

determined through hospital records and obituaries.

tinuity equation, and LVEF was determined by the

The study was carried out under the approval of the

biplane Simpson’s method (19,20). Patients with

Erasmus Medical Center Institutional Review Board.

AVA <1 cm 2 suspected of having pseudo-severe AS

STUDY ENDPOINTS. The primary endpoint of the

were only eligible for this study when DSE revealed an

study was a composite of all-cause death, AVR (i.e.,

AVA >1 cm 2. Exclusion criteria were prior major aortic

SAVR or TAVR), and HF hospitalization. If the patient

surgery, prior surgical aortic valve replacement (SAVR)

was admitted for HF at the time of the index echo-

or transcatheter aortic valve replacement (TAVR),

cardiogram, the first event thereafter was considered

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

T A B L E 2 Therapy at Time of Index Echocardiography (N ¼ 305)

Cardiac resynchronization therapy

38 (13)

Medication use Beta-blocker

216 (73)

ACE inhibitor

143 (48)

an endpoint. Secondary endpoints included the composite of death and rehospitalization as well as each individual component of the primary composite endpoint. STATISTICAL ANALYSIS. Continuous data are pre-

ARB

83 (28)

MRA

62 (21)

sented as mean
SD or confidence intervals (CIs)

Combined beta-blocker, ACE/ARB, and MRA

39 (13)

when applicable, or median and interquartile range

194 (65)

(IQR) depending on distribution. Distribution of data

Digoxin

19 (9)

was checked with histograms and the Shapiro-Wilk

Nitrate

81 (38)

test. Categorical variables were compared with the

Calcium antagonist

99 (34)

chi-square test for trend. Continuous variables at

Statin

223 (75)

Acetylsalicylic acid

196 (66)

different time points were compared using the paired

Oral anticoagulation

129 (43)

Other diuretic agent

P2Y12 receptor inhibitor

71 (24)

Student t test. Cumulative incidence functions of the pre-defined composite endpoint—death, AVR, and HF hospitalization—were determined using the Kaplan-

Values are n (%).

Meier method, with date of the index echocardio-

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; MRA ¼ mineralocorticoid receptor antagonist.

gram as initial time of follow-up (t ¼ 0). Cumulative incidences were evaluated per year of follow-up to

F I G U R E 1 Study Flowchart

Patients with moderate AS and LV systolic dysfunction between 20122015 meeting inclusion criteria N=305

Baseline demographics and echocardiography available - 100% Follow-up echocardiography available - 56%

Clinical follow-up data available - 100% Year 1

Death, AVR, HF hospitalization 24%

Clinical follow-up data available - 80% Year 2

Death, AVR, HF hospitalization 38%

Clinical follow-up data available - 67% Year 3

Death, AVR, HF hospitalization 47%

Clinical follow-up data available - 36% Year 4

Death, AVR, HF hospitalization 61%

In total, 305 patients were identified as having moderate aortic stenosis (AS) and left ventricular (LV) systolic dysfunction by pre-defined criteria. After 4 years of follow-up, 61% of patients reached the primary composite endpoint of all-cause death, aortic valve replacement (AVR), or heart failure (HF) hospitalization. Availability of clinical data decreased as the follow-up time increased due to loss to follow-up. A follow-up echocardiography had been obtained in 56% of the patients.

2385

van Gils et al.

2386

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

the admission date was computed as initial time of

F I G U R E 2 Incidence of the Composite Primary Endpoint

follow-up (t ¼ 0). A log-rank test was applied to compare between-group differences. Univariate and

Death, AVR, or HF hospitalization

multivariate Cox proportional hazard regression an-

100

alyses were performed to identify independent preCumulative Incidence (%)

dictors of the primary composite endpoint. Cox regression was performed in a 2-step hierarchical 61%

fashion to account for potential variation in outcome between institutions. A p value < 0.20 in the uni-

47%

50

38%

variate model was used as an entry criterion for the multivariate model.

24%

Individual components of the primary endpoint were

analyzed

using

the

cumulative

incidence

competing risk method, accounting for death and

0

N at risk: 305

AVR as competing risks (21,22). Data analysis was 193

117

72

33

1

2

3

4

0

performed using SPSS version 21 (IBM, Armonk, New York). A 2-sided, p value < 0.05 was considered

Time (Years)

statistically significant.

Cumulative incidence increased to 61% at 4-year follow-up, with the steepest increase

RESULTS

during the first year following the index echocardiogram. The findings implicated that this population faces a high clinical event rate. Abbreviations as in Figure 1.

The study included 305 patients with baseline echocardiograms between January 2010 and December determine trends in timing of occurrence. Survival analyses for the primary endpoint were stratified for LVEF, New York Heart Association (NYHA) functional class, and HF admission. To determine the cumulative incidence function in patients admitted for HF,

2015. Baseline characteristics are listed in Table 1. The mean age was 73
11 years, and 75% were male. The majority had coronary artery disease, with prior revascularization by percutaneous coronary intervention in 36% and coronary artery bypass grafting (CABG) in 28%. One-third (34%) had NYHA functional class III or IV symptoms at baseline. A total of 23 patients (7.5%) were admitted to the hospital at the

F I G U R E 3 Primary Composite Endpoint at Yearly Intervals

time of the index echocardiogram. In terms of baseline therapy, nearly three-quarters were taking

Death, AVR, or HF hospitalization 50

beta-blocking

agents,

and

one-half

angiotensin-

converting enzyme inhibitors; fewer had angiotensin receptor blockers or mineralocorticoid receptor an-

Cumulative Incidence (%)

40

tagonists in their regimens (Table 2). Overall, 13% of patients received a regimen of beta-blockers, angio-

30

tensin-converting enzyme inhibitors/angiotensin re24%

ceptor

blockers,

and

mineralocorticoid

receptor

antagonists. Cardiac resynchronization therapy was

20 14%

14%

Index echocardiographic parameters are listed in

9%

10

present in 13% of patients. Online Table 1. The mean LVEF was 38
9%; AVA 1.24
0.16 cm 2; indexed aortic valve area (AVAi) (AVA divided by body surface area [BSA]) 0.64


0 N at risk: 305

0

193

117

72

33

0.12 cm 2/m 2; Vmax 2.5
0.4 m/s; peak transaortic

1

2

3

4

gradient 26
8 mm Hg; and mean transaortic

Time (Years)

gradient 14
4 mm Hg. The majority had a mean transaortic gradient <20 mm Hg (81%) or Vmax

According to the cumulative incidence curve per year of follow-up for all-cause death,

<3.0 m/s (84%). DSE was performed in 11% of patients

AVR, or HF hospitalization, the event rate is highest in the first year after diagnosis.

to exclude severe AS and confirm moderate AS. Con-

Abbreviations as in Figure 1.

cerning AVAi, 56% of patients had an AVAi 0.6 to 0.9 cm 2/m 2 versus 33% with AVAi <0.6 cm 2/m 2. One-fifth

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

of patients with AVAi 0.6 to 0.9 cm2/m 2 presented with a body mass index >30 kg/m 2 versus 50% of

2387

LVSD and Moderate Aortic Stenosis

F I G U R E 4 Composite Primary Endpoint Stratified by HF Hospitalization

patients with AVAi <0.6 cm 2/m 2.

Death, AVR, or HF hospitalization 100 Log-rank: p<0.001

for 80% of patients beyond 1 year after the index echocardiogram, for 67% beyond 2 years, and for 36% beyond 3 years (Figure 1). The median follow-up time was 638 days (IQR: 280 to 1,137 days). At 4-year follow-up, the event rate for the primary composite endpoint was 61% (95% CI: 54.38% to 67.78%) (Figure 2). The primary composite endpoint appeared to occur predominantly in the first year after the index echocardiogram compared with the years

Cumulative Event Rate (%)

PRIMARY ENDPOINT. Follow-up data were available

60% 50%

50 34% 21%

0

thereafter (Figure 3). The event rate was higher in patients with HF admission at time of the index

N at risk: 45 282

0

echocardiogram compared with the overall cohort

19 185

10 105

1

2

Time (Years)

(log-rank p < 0.001) (Figure 4).

Hospitalized for HF

The univariate analysis is presented in Online

Not hospitalized for HF

Figure 1. Male sex (hazard ratio [HR]: 1.75; 95% CI: 1.16 to 2.64; p ¼ 0.008), diabetes (HR: 1.51; 95% CI: 1.09 to 2.10; p ¼ 0.014); chronic lung disease (HR: 1.59; 95% CI: 1.11 to 2.29; p ¼ 0.012), NYHA functional class III or

During the first 2 years of follow-up, patients who were hospitalized at time of index echocardiogram appeared to be more prone to clinical events than those who were not hospitalized at that time. (For patients admitted for HF, date of admission is t ¼ 0) Abbreviations as in Figure 1.

IV (HR: 2.86; 95% CI: 1.70 to 4.24; p < 0.001), and Vmax (HR: 2.24 per 1 m/s increment; 95% CI: 1.47 to 3.42; p < 0.001) emerged as main predictors for the composite primary endpoint by multivariate analysis

to 31.44%) (Figure 7D), including SAVR in 63%

(Figure 5). Patients with baseline NYHA functional

and TAVR in 37%. The majority of SAVRs did not

class III or IV symptoms had a 4-year event rate of 84%

involve simultaneous CABG (31 of 37; 84%). The me-

(95% CI: 76.92% to 89.21%), compared with 54% for

dian time to SAVR or TAVR was 133 days (IQR: 22 to

NYHA functional class II (95% CI: 41.65% to 64.81%;

543 days).

log-rank p < 0.001) and 45% for NYHA functional class I (95% CI: 25.77% to 61.90%; log-rank p < 0.001)

ECHOCARDIOGRAPHY AT FOLLOW-UP. More than

(Figure 6). There was no statistically significant dif-

one-half of the patients (172 of 305; 56%) underwent a

ference in event rate for patients with an LVEF #35%

follow-up echocardiogram before the study end date.

compared with patients with an LVEF >35% (4-year

The median time between the index echocardiogram

follow-up: 71% vs. 55%; log-rank p ¼ 0.092) (Online

and follow-up echocardiogram was 541 days (IQR: 337

Figure 2). When we divided the study population in

to 890 days) and 467 days (IQR: 315 to 937 days) for

tertiles based on AVAi, we could not detect any dif-

patients who were medically treated and underwent

ference in event rate (log-rank p ¼ 0.107) (Online

AVR, respectively. During follow-up, AVA decreased

Figure 3). The event rates were similar among the 4

on average from 1.24
0.16 cm 2 to 1.14
0.25 cm 2

individual institutions (log-rank p ¼ 0.515) (Online

(p < 0.001) in patients who were medically treated

Figure 4).

and from 1.23
0.14 cm 2 to 1.00
0.22 cm 2

At 4-year follow-up, the rate of the composite of

(p ¼ 0.004) in patients who underwent subsequent

all-cause death or HF hospitalization was 48% (95%

AVR. The evolution of echocardiographic parameters

CI: 40.65% to 56.61%) (Figure 7A), all-cause death was

is displayed in Online Table 1.

36% (95% CI: 28.68% to 44.80%) (Figure 7B), and cumulative HF hospitalization rate was 27% (95% CI:

DISCUSSION

20.32% to 35.67%) (Figure 7C). New hospital admissions for HF occurred in 43% of patients who were

This longitudinal multicenter cohort study reported

admitted for HF at time of index echocardiogram

the clinical outcome of consecutive patients with

(n ¼ 23) versus 4% in patients who were not admitted

moderate AS and LV systolic dysfunction. The main

for HF at time of index echocardiogram (n ¼ 282)

findings can be summarized as follows: 1) the com-

(p < 0.001). The rate of AVR was 24% (95% CI: 18.96%

posite primary endpoint of all-cause death, AVR, or

van Gils et al.

2388

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

F I G U R E 5 Multivariate Cox Regression Analysis

Death, AVR, or HF hospitalization Adjusted HR 1.63 1.00*

Male Female

95% CI [1.07-2.48]

P-value 0.022

Diabetes No diabetes

1.28 1.00*

[0.91-1.80]

0.150

Chronic lung disease No chronic lung disease

1.36 1.00*

[0.93-1.98]

0.111

NYHA III or IV NYHA II NYHA I

2.40 1.40 1.00*

[1.47-3.90] [0.85-2.30]

<0.001 0.191

HF admission when diagnosed No HF admission when diagnosed

1.37 1.00*

[0.71-2.64]

0.345

AVA<1.25 cm2 AVA >1.25 cm2

1.11 1.00*

[0.77-1.59]

0.574

2.28

[1.48-3.52]

<0.001

V max 0

2

4

6

Hazard Ratio

A 2-step hierarchical multivariate Cox regression model was conducted to evaluate predictors for the primary composite endpoint; the purpose of the hierarchical structure was to account for variation between institutions. Variables were selected if they met the entry criterion in univariate regression. *Reference category. AVA ¼ aortic valve area; CI ¼ confidence interval; HR ¼ hazard ratio; NYHA ¼ New York Heart Association; Vmax ¼ peak aortic jet velocity; other abbreviations as in Figure 1.

HF hospitalization occurred in 61% of patients at

events; 3) most events occurred during the first year

4-year follow-up; 2) male sex, NYHA functional class

after the diagnosis; and 4) patients admitted for HF at

III or IV, and higher transaortic Vmax on the index

time of inclusion were particularly vulnerable and

echocardiogram were independent predictors of

had event rates of 50% and 60% at 1 and 2 years, respectively (Central Illustration). The combination of moderate AS and LV systolic

F I G U R E 6 Composite Primary Endpoint Stratified by NYHA Functional Class

dysfunction in the general population is likely Death, AVR, or HF hospitalization

under-reported and is expected to grow with an

100

aging population. A large population-based study

Cumulative Incidence (%)

Log-rank: p<0.001

84%

58% 54%

50 36%

31%

39%

45%

35% 18%

N at risk: 98 128 79

0

as 2.8% (23). The inverse relationship between LV wall stress and ejection fraction may at least partly explain LV systolic dysfunction (24), and onequarter of all patients with AS have LV systolic dysfunction (25).

23%

16%

0

concluded that the prevalence of moderate or severe AS in patients $75 years of age was as high

67%

AS progression in our study was illustrated by an 25 56 36

55 83 55

1

15 37 20

3

2

5 18 10

is in keeping with the 0.1 cm 2 average annual AVA

4

for AVR at 1-year follow-up was higher than previously

NYHA II

decrease reported in previous studies (8,9). The need reported in patients with asymptomatic severe AS

Time (Years) NYHA III or IV

annual AVA decrease by 0.10 cm2 to 0.24 cm 2, and

NYHA I

(13% vs. 5% to 9%) (8,26) or moderate AS and preserved LV function (13% vs. 4% to 8%) (15,16,18,27).

Patients in NYHA functional class III or IV had a worse prognosis compared with patients

Although the decision to intervene could not be

in lower NYHA functional classes. Abbreviations as in Figures 1 and 5.

determined from this retrospective study (e.g., clinical HF, progression of AS, progressive symptoms),

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

2389

LVSD and Moderate Aortic Stenosis

F I G U R E 7 Competing Risk Curves for Individual Endpoints

All-cause death or HF hospitalization

A 50

39%

40 Cumulative Incidence (%)

Cumulative Incidence (%)

50

48%

40 28% 30

16%

20

All-cause death

B

30 25%

10

0

0 1

3

2

18%

20

10

0

36%

4

9%

0

1

Time (Years) HF hospitalization 50

50

40

40

30 27% 23%

20 15% 9%

10

4

AVR

D

Cumulative Incidence (%)

Cumulative Incidence (%)

C

3

2 Time (Years)

30 24% 17%

20

20%

13% 10

0

0 0

1

2

3

4

0

1

Time (Years)

2

3

4

Time (Years)

A cumulative incidence competing risk analysis was conducted to evaluate the cumulative incidence of the individual components of the primary endpoint: (A) all-cause death and HF hospitalization; (B) all-cause death; (C) HF hospitalization; and (D) AVR. The individual endpoints were all common, confirming that the occurrence of clinical events in patients with moderate AS and LV systolic dysfunction is multifactorial. Abbreviations as in Figure 1.

it might suggest accelerated clinical deterioration in patients with moderate AS and LV dysfunction.

Similar to HF studies, symptoms but not LVEF were a strong predictor for clinical events (29,30). Patients in

The rates for all-cause death and hospitalization

NYHA functional class III or IV had significantly more

for HF were 25% and 26% respectively at 3-year

events than patients in NYHA functional class II or I

follow-up. In recent large HF trials enrolling symp-

(primary composite endpoint 84% vs. 54% and 45%,

tomatic patients with an LVEF #35%, 3-year rates for

respectively; p < 0.001). Patients admitted for HF at

HF admissions and all-cause death were <20% and

the time of the index echocardiogram had a 2-fold

25%, respectively (28). The higher event rates in the

higher 1-year event rate, including significantly more

current study might suggest that the presence of

admissions for HF (43% vs. 4%; p < 0.001).

moderate AS in patients with LV systolic dysfunction negatively affects overall prognosis.

The true effect of moderate AS in patients with LV systolic dysfunction remains unknown, although

2390

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

C E NT R AL IL L U STR AT IO N Moderate Aortic Stenosis and LV Systolic Dysfunction

van Gils, L. et al. J Am Coll Cardiol. 2017;69(19):2383–92.

Patients with left ventricular (LV) systolic dysfunction (left ventricular ejection fraction [LVEF] 20% to 50%) and concomitant moderate aortic stenosis (aortic valve area [AVA] 1.0 to 1.5 cm2) are at high risk for clinical events, including all-cause death and hospitalization for heart failure. Currently, aortic valve replacement is not indicated in these patients, although they may receive benefit. This premise will be studied in the randomized TAVR-UNLOAD (Transcatheter Aortic Valve Replacement to Unload the Left Ventricle in Patients with Advanced Heart Failure) trial.

indirect evidence suggests survival benefit with AVR.

exploration

In the TOPAS (True or Pseudo Severe Aortic Stenosis)

Indeed, TAVR has become an attractive, minimally

observational cohort study, an AVA <1.2 cm 2 as

invasive alternative to SAVR for patients with severe

opposed to AVA <1 cm 2 was associated with mortality

AS and intermediate or greater surgical risk (39–43).

in medically treated patients with low-flow, low-

Early

gradient AS (31–34). A retrospective analysis from the

reduction and thus affect clinical outcome in pa-

Duke Echocardiographic Database reported a mortal-

tients with moderate AS and LV systolic dysfunction.

ity benefit associated with AVR (with or without

This premise will be studied in the randomized

concomitant CABG) for moderate AS in patients with

TAVR

LV systolic dysfunction (35). Finally, moderate

Replacement to Unload the Left Ventricle in Patients

prosthesis/patient

with Advanced Heart Failure) trial (NCT02661451)

mismatch

after

AVR,

which

generally corresponds to residual moderate AS, has

TAVR

of

early

may

UNLOAD

TAVR

provide

in

this

population.

additional

(Transcatheter

afterload

Aortic

Valve

(44).

been associated with increased risk of early and late mortality in patients with LV systolic dysfunction

STUDY LIMITATIONS. The retrospective design of the

(36–38). In aggregate, patients with moderate AS and

study might introduce selection bias. Although all

LV systolic dysfunction might be more vulnerable to

patients in our study shared the common denomina-

the increased LV afterload imposed by AS and, thus,

tor of moderate AS and LV systolic dysfunction, the

benefit from AVR. The high event rate in these pa-

population was heterogeneous. There were multiple

tients warrants further research and may justify the

underlying causes of LV systolic dysfunction, and

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

there were diverse therapeutic regimens in this

interpretation was incorrect and patients had true

multinational population. Not all patients were

severe AS rather than moderate AS. Patients in whom

necessarily treated with optimal HF therapy. This

the DSE revealed true severe AS were not included

might be partly explained by the fact that one-quarter

because

low-flow,

of patients were in NYHA functional class I and might

beyond

the

never have had HF symptoms.

Although this retrospective study reflected contem-

scope

low-gradient of

this

severe

AS

retrospective

falls

study.

Furthermore, we elected to define moderate AS

porary practice in 4 academic institutions, some pa-

according to the parameters (AVA, mean gradient,

tients might have had severe AS based on indexed

and peak velocity) and cut-off values proposed in the

AVA and might have benefitted from AVR at an earlier

guidelines (13). Using AVAi to determine AS severity

stage.

might have reclassified some patients with large BSA from moderate to severe AS (if AVAi is $0.6 cm 2/m2 ).

CONCLUSIONS

Conversely, patients with small BSA might have been reclassified from mild AS (based on AVA) to moderate

Patients with concomitant moderate AS and LV

AS (based on AVAi). However, 1 of the important

systolic dysfunction are at high risk for clinical

limitations of AVAi is that it may overestimate AS

events. Further studies are needed to determine if

severity in obese patients. In this regard, one-half of

earlier AVR in these patients might improve clinical

2

2

the patient population with AVAi <0.6 cm /m in our

outcome.

2

series had a body mass index >30 kg/m versus 20% of patients with AVAi $0.6 cm 2/m 2. Furthermore, a

ADDRESS FOR CORRESPONDENCE: Dr. Nicolas M.

recent study suggested using lower cutoff values for

Van Mieghem, Department of Interventional Cardiology,

AVAi to define severe AS (45). Hence, further studies

Thoraxcenter, Erasmus Medical Center, Room Bd 171,

are needed to refine the method of indexation of AVA

‘s Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.

in patients with AS to achieve more accurate estima-

E-mail: [email protected].

tion of AS severity. Nevertheless, this database likely reflected real-life practice and underscored the complexity of AS diagnosis and HF treatment. A propensity-matched analysis versus patients with LV dysfunction without AS could further clarify the added burden of moderate AS in patients with LV

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Patients with LV systolic dysfunction and moderate aortic valve stenosis face an

dysfunction. Finally, the decision to proceed with AVR in our study was undertaken by the treating physician and might reflect center-specific practices. DSE was performed in 11% of patients. It may be possible that we failed to include more patients with pseudo-severe (and thus moderate) AS because the treating physi-

elevated risk of adverse events despite medical therapy for HF. TRANSLATIONAL OUTLOOK: Further studies are needed to determine whether combining TAVR with medical therapy for HF improves clinical outcomes in patients with LV systolic dysfunction and moderate aortic valve stenosis.

cian did not perform a DSE. It is also possible that DSE

REFERENCES 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. 2. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012;33: 1787–847. 3. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a

community-based population. JAMA 2004;292: 344–50.

public health problem. Heart Fail Clin 2006;2: 379–93.

4. Levy D, Kenchaiah S, Larson MG, et al. Longterm trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–402.

8. Otto CM, Burwash IG, Legget ME, et al. Pro-

5. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. 6. Carabello BA. Evaluation and management of patients with aortic stenosis. Circulation 2002; 105:1746–50. 7. Supino PG, Borer JS, Preibisz J, Bornstein A. The epidemiology of valvular heart disease: a growing

spective study of asymptomatic valvular aortic stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95: 2262–70. 9. Palta S, Pai AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 2000; 101:2497–502. 10. Huber D, Grimm J, Koch R, Krayenbuehl HP. Determinants of ejection performance in aortic stenosis. Circulation 1981;64:126–34.

2391

2392

van Gils et al.

JACC VOL. 69, NO. 19, 2017 MAY 16, 2017:2383–92

LVSD and Moderate Aortic Stenosis

11. Ross J Jr., Braunwald E. Aortic stenosis. Circulation 1968;38:61–7. 12. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33: 2451–96. 13. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. 14. Iivanainen AM, Lindroos M, Tilvis R, Heikkila J, Kupari M. Natural history of aortic valve stenosis of varying severity in the elderly. Am J Cardiol 1996;78:97–101.

24. Dineen E, Brent BN. Aortic valve stenosis: comparison of patients with to those without chronic congestive heart failure. Am J Cardiol 1986;57:419–22. 25. Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol 2013;62:1002–12. 26. Taniguchi T, Morimoto T, Shiomi H, et al. Initial surgical versus conservative strategies in patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2015;66:2827–38.

mismatch on short-term mortality after aortic valve replacement. Circulation 2003;108:983–8. 37. Mohty D, Malouf JF, Girard SE, et al. Impact of prosthesis-patient mismatch on long-term survival in patients with small St Jude Medical mechanical prostheses in the aortic position. Circulation 2006;113:420–6. 38. Mohty D, Dumesnil JG, Echahidi N, et al. Impact of prosthesis-patient mismatch on long-term survival after aortic valve replacement: influence of age, obesity, and left ventricular dysfunction. J Am Coll Cardiol 2009;53: 39–47.

27. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359:1343–56.

39. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.

aortic valve stenosis. Eur Heart J 1988;9 Suppl E: 57–64.

28. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus ena-

16. Kennedy KD, Nishimura RA, Holmes DR Jr., Bailey KR. Natural history of moderate aortic stenosis. J Am Coll Cardiol 1991;17:313–9.

lapril in heart failure. N Engl J Med 2014;371: 993–1004.

40. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364: 2187–98.

15. Horstkotte D, Loogen F. The natural history of

17. Rosenhek R, Klaar U, Schemper M, et al. Mild and moderate aortic stenosis. Natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199–205. 18. Gohlke-Barwolf C, Minners J, Jander N, et al. Natural history of mild and of moderate aortic stenosis-new insights from a large prospective European study. Curr Probl Cardiol 2013;38: 365–409. 19. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39.e14. 20. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–70. 21. Ghali WA, Quan H, Brant R, et al. Comparison of 2 methods for calculating adjusted survival curves from proportional hazards models. JAMA 2001;286:1494–7. 22. Verduijn M, Grootendorst DC, Dekker FW, Jager KJ, le Cessie S. The analysis of competing events like cause-specific mortality—beware of the Kaplan-Meier method. Nephrol Dial Transplant 2011;26:56–61. 23. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a populationbased study. Lancet 2006;368:1005–11.

29. Mangla A, Kane J, Beaty E, Richardson D, Powell LH, Calvin JE Jr. Comparison of predictors of heart failure-related hospitalization or death in patients with versus without preserved left ventricular ejection fraction. Am J Cardiol 2013;112:1907–12. 30. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355: 260–9. 31. Clavel MA, Burwash IG, Mundigler G, et al. Validation of conventional and simplified methods to calculate projected valve area at normal flow rate in patients with low flow, low gradient aortic stenosis: the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. J Am Soc Echocardiogr 2010;23:380–6. 32. Clavel MA, Fuchs C, Burwash IG, et al. Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study. Circulation 2008;118:S234–42. 33. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. J Am Soc Echocardiogr 2009;22:1–23, quiz 101–2. 34. Baumgartner H, Hung J, Bermejo J, et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:1–25. 35. Samad Z, Vora AN, Dunning A, et al. Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction. Eur Heart J 2016;37:2276–86. 36. Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P. Impact of valve prosthesis-patient

N Engl J Med 2010;363:1597–607.

41. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014; 370:1790–8. 42. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016; 374:1609–20. 43. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 2016;387: 2218–25. 44. Spitzer E, Van Mieghem NM, Pibarot P, et al. Rationale and design of the Transcatheter Aortic Valve Replacement to UNload the Left ventricle in patients with ADvanced heart failure (TAVR UNLOAD) trial. Am Heart J 2016;182:80–8. 45. Tribouilloy C, Bohbot Y, Marechaux S, et al. Outcome implication of aortic valve area normalized to body size in asymptomatic aortic stenosis. Circ Cardiovasc Imaging 2016;9:e005121.

KEY WORDS heart failure, outcomes, peak aortic jet velocity, surgical aortic valve replacement, transcatheter aortic valve replacement

A PPE NDI X For a supplemental table and figures, please see the online version of this article.