Download Heart Failure With Improved Ejection Fraction: Clinical

Original Article
Heart Failure With Improved Ejection Fraction: Clinical
Characteristics, Correlates of Recovery, and Survival
Results From the Valsartan Heart Failure Trial
Viorel G. Florea, MD, PhD, DSc; Thomas S. Rector, PhD;
Inder S. Anand, MD, FRCP, D.Phil (Oxon.); Jay N. Cohn, MD
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
Background—Heart failure with recovered or improved ejection fraction (HFiEF) has been proposed as a new category of
HF. Whether HFiEF is clinically distinct from HF with persistently reduced ejection fraction remains to be validated.
Methods and Results—Of the 5010 subjects enrolled in the Valsartan Heart Failure Trial (Val-HeFT), 3519 had a baseline
left ventricular EF of <35% and a follow-up echocardiographic assessment of EF at 12 months. Of these, 321 (9.1%)
patients who had a 12-month EF of >40% constituted the subgroup with HFiEF. EF improved from 28.7±5.6% to
46.5±5.6% in the subgroup with HFiEF and remained reduced (25.2±6.2% and 27.5±7.1%) in the subgroup with HF
with reduced ejection fraction. The group with HFiEF had a less severe hemodynamic, biomarker, and neurohormonal
profile, and it was treated with a more intense HF medication regimen. Subjects who had higher blood pressure and those
treated with a β-blocker or randomized to valsartan had greater odds of being in the HFiEF group, whereas those with an
ischemic pathogenesis, a more dilated left ventricle, and a detectable hs-troponin had lower odds of an improvement in
EF. Recovery of the EF to >40% was associated with a better survival compared with persistently reduced EF.
Conclusions—Our data support HFiEF as a stratum of HF with reduced ejection fraction with a more favorable outcome,
which occurs in a minority of patients with HF with reduced ejection fraction who have a lower prevalence of ischemic
heart disease, a less severe hemodynamic, biomarker, and neurohormonal profile, and who are treated with a more intense
HF medication regimen.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336. (Circ Heart Fail. 2016;9:e003123. DOI: 10.1161/CIRCHEARTFAILURE.116.003123.)
Key Words: biomarker
■
blood pressure
C
urrent guidelines for the management of heart failure
(HF) divide patients with HF into 2 categories: those with
reduced ejection fraction (EF of ≤40%; HFrEF) and those
with preserved ejection fraction (>40%; HFpEF).1 It has been
recognized that a subset of patients with HFpEF previously
had HFrEF.2 These patients with recovery or improvement in
EF (HFiEF) may be clinically distinct from those with persistently preserved or reduced EF.1,2
■
heart failure
■
prognosis
■
valsartan
In this post hoc analysis of the Valsartan Heart Failure
Trial (Val-HeFT)5 database, we characterized the subjects who
had improved their EF during the first 12 months of follow-up,
evaluated the independent correlates of EF improvement, and
determined whether their all-cause mortality was substantially
different from the subjects whose EF remained reduced.
Methods
See Editorial by Basuray and Fang
See Clinical Perspective
Study Design and Patient Selection
Val-HeFT was a randomized, placebo-controlled, double-blind trial
that enrolled 5010 patients with New York Heart Association functional class II to IV HF and an EF of <40% designed to evaluate the
efficacy of valsartan. All-cause mortality was one of the 2 primary
Val-HeFT end points5. Valsartan treatment did not exhibit a statistically significant effect on mortality, but stratification by baseline severity of left ventricular remodeling influenced the results. Patients
with worse left ventricular internal diastolic diameter (LVIDd) and
EF were at highest risk of an event and gained the most antiremodeling effect and clinical benefit with valsartan treatment.6 Val-HeFT
was approved by the institutional review board at each center, and all
subjects provided a written informed consent.
In 2011, Punnoose et al2 reported that nearly 70% of
patients with symptomatic HFpEF had recovered from a previously low EF. These patients were clinically distinct from
those with HFpEF and more similar to the HFrEF population
from which they initially arose. Further studies found that
HFiEF is associated with a better biomarker profile, quality
of life, and event-free survival than continued HFrEF and
HFpEF3,4 but still experience a significant number of HF hospitalizations, suggesting persistent HF risk.3
Received January 25, 2016; accepted May 27, 2016.
From the Division of Cardiology (V.G.F., I.S.A.) and Center for Chronic Disease Outcomes Research (T.S.R), Minneapolis Veterans Affairs Health
Care System, MN; and Department of Medicine, University of Minnesota, Minneapolis (V.G.F., T.S.R., J.N.C.).
Correspondence to Viorel G. Florea, MD, PhD, DSc, Department of Medicine, Minneapolis VA Health Care System, Cardiology 111C, One Veterans Dr,
Minneapolis, MN 55417. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.116.003123
1
2 Florea et al Heart Failure With Improved Ejection Fraction
Table 1. Baseline Characteristics of Study Participants
HFiEF
(n=321)
HFrEF
(n=3198)
61±11
62±11
HFiEF
(n=321)
HFrEF
(n=3198)
P Value
Spironolactone, %
4
5
0.50
Digoxin, %
66
68
0.48
P Value
Demographics and History
Age, y (mean±SD)
Table 1. Continued
0.02
Male sex, %
74
80
0.02
Diuretics, %
82
86
0.05
White race, %
90
90
0.86
Aspirin, %
38
40
0.54
Ischemic pathogenesis, %
37
56
<0.001
Statin, %
26
33
0.01
H/o diabetes mellitus, %
24
25
0.62
Amiodarone, %
11
13
0.18
H/o hypertension, %
12
6
<0.001
H/o atrial fibrillation, %
15
11
0.07
H/o COPD, %
10
12
0.20
Symptoms and physical examination
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NYHA class III or IV, %
34
37
0.34
Orthopnea, %
26
28
0.44
Edema, %
19
16
0.22
PND, %
7
8
0.27
S3, %
22
26
0.09
JVD, %
13
13
0.72
Rales, %
10
11
0.77
Systolic BP, mm Hg
127±20
124±18
<0.001
Diastolic BP, mm Hg
78±12
76±10
<0.01
Heart rate, beats per minute
74±13
73±12
0.49
BMI, kg/m
27±5
27±4
0.86
LVEF, %
28.7±5.6
25.2±6.2
<0.001
LVIDd/BSA, cm/m2
3.5±0.5
3.7±0.5
<0.001
4±2
4±2
0.92
Hemoglobin, g/dL
14±1
14±1
0.45
Hematocrit, %
41±5
41±4
0.32
Sodium, mmol/L
140±3
139±3
<0.05
Potassium, mmol/L
4.4±0.6
4.4±0.6
0.28
Total protein, g/dL
72±5
72±6
0.62
Albumin, g/dL
4.2±0.3
4.2±0.3
0.19
Creatinine, mmol/L
107±22
112±26
<0.001
7±3
8±3
<0.01
62±15
59±16
<0.001
2
Clinical chemistry
BUN, mg/dL
eGFR, mL/min per 1.73 m2
Uric acid, mg/dL
Echocardiographic Measurements of Left
Ventricular Performance
Echocardiography, both the recording and interpretation, was carried out at 291 multinational sites. Participation in the trial was
dependent on meeting specific core laboratory standards for recording and reading of LVIDd from 2 dimensionally directed M-mode
echocardiography, and EF was derived from LV volumes using the
area–length method.7 During the trial, quality control was monitored
from random sampling of patient studies, and this was satisfactorily
maintained.8 Serial echocardiograms in 5010 patients were obtained
at baseline before randomization and at 4, 12, 18, 24, and 30 months
after randomization.
Biochemical Measurements
Echocardiography
Neutrophils, %
ACE indicates angiotensin-converting enzyme; BMI, body mass index; BNP,
B-type natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; COPD,
chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate;
HFiEF, heart failure with improved ejection fraction; H/o, history of; HFrEF, heart
failure with reduced ejection fraction; JVD, jugular venous distention; LVEF, left
ventricular ejection fraction; LVIDd/BSA, left ventricular internal diastolic dimension
corrected for body surface area; NYHA, New York Heart Association; PND,
paroxysmal nocturnal dyspnea; S3, third heart sound; and WBC, white blood cell.
7±2
7±2
0.22
Cholesterol, mg/dL
211±48
204±48
0.01
Triglycerides, mg/dL
197±193
190±175
0.48
Medications
ACE-inhibitor, %
93
93
0.68
Valsartan,%
58
49
<0.01
β-Blocker, %
47
34
<0.001
(Continued )
A complete blood cell count and measurements of serum albumin,
uric acid, creatinine, and blood urea nitrogen were performed at a
central laboratory with a commercially automated system at randomization and after 4, 6, 12, 18, and 24 months. Glomerular filtration
rate was estimated using the Modification of Diet in Renal Disease
equation.9 Other variables used in this analysis included neurohormones (B-type natriuretic peptide [IRMA Shionogi] and N-terminal
probrain natriuretic peptide [ECLIA Elecsys 2010 analyzer, Roche
Diagnostics]) measured by commercially available assays,10 norepinephrine [high-performance liquid chromatography with electrochemical detection],11 endothelin I, big endothelin, plasma renin
activity and aldosterone [by radioimmunoassay], high-sensitivity troponin T,12 high-sensitivity C-reactive protein,13 galectin-3,14 soluble
ST2,15 and growth-differentiating factor 15.16
Statistical Analysis
Distributions of continuous variables are described using means and
SDs and categorical variables as proportions expressed as percentages. Highly skewed continuous distributions are described by the
median and the interquartile range and were transformed using natural logarithms for regression analyses. Baseline characteristics of the
HFiEF and continued HFrEF groups were compared using a t test,
Rank-sum test or χ2 test as appropriate for the level of measurement
and distribution of the variable.
Stepwise forward and backward logistic regression with a P value
<0.10 required for entry or removal was used to identify independent
correlates of substantial improvements in EF forcing the baseline EF
into the model to help control for the inverse relationship between
baseline EF measurements and changes in EF. First, all 42 baseline
variables described in Table 1 were tested along with an indicator of
subjects in the United States. Then the baseline neurohormones and
cardiac biomarkers listed in Table 2 that were measured in at least
3 Florea et al Heart Failure With Improved Ejection Fraction
80% of 3519 subjects (norepinephrine, plasma renin activity, aldosterone, B-type natriuretic peptide, C-reactive protein, and troponin)
were tested for addition to the 7 independent correlates from Table 1.
These regression analyses were clustered by the study center to estimate robust SEs. Discrimination provided by the logistic regression
model containing the independent correlates was examined by the estimated probabilities of being in the HFiEF group and the area under
the receiver operating characteristic curve.
Survival in the HFiEF and continued HFrEF groups after month 12
is compared using Kaplan–Meier curves and the log-rank test. Mortality
rates per 100 person-years were calculated, and the incidence rate ratio
was estimated using Poisson regression clustered by the study center.
The group discrimination of times to death was assessed by Harrell
C index. A P value of <0.05 was considered statistically significant
without adjustment for the number of comparisons being made during
these exploratory analyses of data from a randomized controlled clinical trial. All analyses were done using version 12.1 of Stata software.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the article as
written.
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Results
Changes in Ejection Fraction
Of the 5010 patients enrolled into Val-HeFT, 4997 patients
had an echocardiographic assessment of left ventricular EF at
baseline. Of these, 4410 met our cohort inclusion criteria of a
baseline EF of <35%. Of the 4410 patients, 3519 (80%) had a
12-month EF and were included in our analysis. Of these, 321
patients (9.1%) who had a 12-month EF of >40% constituted
the subgroup of patients with HFiEF, and 3198 patients (90.9%)
who had a 12-month EF of ≤40% constituted the subgroup
of patients with HFrEF. The EF improved from 28.7±5.6%
to 46.5±5.6% in the subgroup of patients with HFiEF and
remained reduced (25.2±6.2% and 27.5±7.1%) in the comparison group. The 12-month changes in EF were 17.8±8.0%
(range, 6%–42%) in the HFiEF group and 2.3±6.7% (range,
−27 to 27) in the continued HFrEF group. A significant difference in changes in EF between the subgroups of patients
with HFiEF and HFrEF was observed by 4 months after the
baseline assessment (8.8±9.0% versus 2.3±6.5% respectively,
P<0.001), indicating earlier changes in EF in the 2 subgroups
of patients were consistent in their direction and magnitude.
Baseline Clinical Characteristics
Baseline demographic and clinical characteristics of the study
groups with HFiEF and HFrEF are compared in Table 1. Overall, the group with HFiEF had features of less severe HF with
higher baseline left ventricular EF and lower baseline LVIDd
normalized to body surface area (LVIDd/BSA). This group was
marginally younger and less likely to be of male sex compared
with the group with HFrEF. Fewer patients in the HFiEF group
had an ischemic origin of HF. This group had a higher prevalence of hypertension but a similar prevalence of diabetes mellitus, atrial fibrillation, or chronic obstructive pulmonary disease.
Apart from a higher systolic and diastolic blood pressure, subjects with HFiEF had a similar symptomatic profile in respect
to orthopnea, edema, paroxysmal nocturnal dyspnea, third heart
sound, jugular venous distention, pulmonary rales, heart rate,
and prevalence of New York Heart Association class III or IV.
Clinical chemistry variables were not different between the 2
groups except for better markers of renal function (creatinine,
blood urea nitrogen, and glomerular filtration rate) and higher
serum sodium and cholesterol levels in the HFiEF group. More
subjects with HFiEF were treated with valsartan and a β-blocker,
and fewer subjects with HFiEF were treated with a statin.
Neurohormones and Cardiac Biomarkers
Available baseline levels of plasma neurohormones and cardiac
biomarkers in each of the HF category are presented in Table 2.
Overall, the HFiEF group had less severe neurohormonal activation. Plasma norepinephrine, plasma renin activity (PRA),
endothelin I, big endothelin, B-type natriuretic peptide, and
N-terminal probrain natriuretic peptide were significantly lower
in the HFiEF group compared with the HFrEF group. Plasma
aldosterone level was also lower in the HFiEF group, but the
Table 2. Neurohormones and Cardiac Biomarkers in Study Participants*
HFiEF, n=321
Norepinephrine, pg/mL
PRA, ng/mL per hour
HFrEF, n=3198
P Value
352 (257–505), n=264
381 (270–562), n=2784
0.04
4 (1–12), n=267
5 (2–16), n=2777
<0.01
Aldosterone, pg/mL
94 (62–160), n=243
103 (63–177), n=2638
0.22
Endothelin I, pg/mL
1.0 (0.5–2.4), n=115
1.6 (0.8–2.8), n=1276
<0.01
Big Endothelin, pg/mL
0.8 (0.6–0.9), n=152
0.8 (0.6–1.0), n=1502
0.03
BNP, pg/mL
61 (24–166), n=267
99 (42–234), n=2783
<0.001
565 (224–1386), n=249
903 (393–1910), n=2638
<0.001
NT-proBNP, pg/mL
hs-CRP, mg/L
3 (1–7), n=257
3 (1–7), n=2740
0.62
hs-TnT, ng/mL
9 (4–16), n=247
13 (6–22), n=2606
<0.001
Gal-3, ng/mL
15 (13–19), n=100
16 (13–21), n=1082
0.07
GDF-15, ng/L
sST2, ng/mL
1757 (1314–2501), n=105
22 (16–30), n=100
2018 (1410–2950), n=1147
24 (19–33), n=1081
0.02
0.02
BNP indicates B-type natriuretic peptide; Gal-3, galectin-3; GDF growth-differentiating factor; HFiEF, heart failure with improved
ejection fraction; HFrEF, heart failure with reduced ejection fraction; hs-CRP, high-sensitivity C-reactive protein; hs-TnT, highsensitivity troponin T; NT-proBNP, aminoterminal probrain natriuretic peptide; PRA, plasma renin activity; and sST2, soluble ST2.
*Because of skewed distribution, values are presented as median (Quartile 2–Quartile 3).
4 Florea et al Heart Failure With Improved Ejection Fraction
of 3 years with a median (interquartile range) of 2 (1.6–2.4)
years beyond month 12. During this period, 397 (11.3%) subjects died. Figure shows the Kaplan–Meier survival curves for
the HFiEF and continued HFrEF groups. As seen, the proportion surviving was significantly higher in the HFiEF group
(log-rank P value=0.005). The mortality rate was 2.9 per 100
person-years (95% confidence interval, 1.8–4.5) in the HFiEF
group and 5.8 per 100 person-years (95% confidence interval,
5.3–6.4) in the continued HFrEF group. The unadjusted mortality rate ratio for HFiEF was 0.49 (95% confidence interval,
0.31–0.76; P=0.002). Harrell concordance statistic was 0.52,
indicating HFiEF did not discriminate times to death.
Figure. Kaplan–Meier curves of time to death in patients with
heart failure with reduced ejection fraction (HFrEF) and those with
improved ejection fraction (HFiEF).
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 2, 2017
difference did not reach statistical significance. The HFiEF group
was also characterized by lower levels of B-type natriuretic peptide and N-terminal probrain natriuretic peptide, high-sensitivity
troponin T, growth-differentiating factor 15, and soluble ST2.
There was also a trend toward a lower level of galectin-3 in the
HFiEF group, but there was no difference in the levels of highsensitivity C-reactive protein between the 2 HF groups.
Independent Correlates of Recovery of Ejection
Fraction
The stepwise forward and backward logistic regression analysis that forced the baseline EF into the model (n=3511) identified 7 variables that were independent correlates of HFiEF:
male sex (odds ratio [OR], 0.69), ischemic pathogenesis (OR,
0.41), body mass index (OR, 0.96), diastolic blood pressure
(OR, 1.01), LVIDd/BSA (OR, 0.5), β-blocker therapy at baseline (OR, 1.9), and treatment with valsartan (OR, 1.5). Subjects who had higher blood pressure and those treated with a
β-blocker or randomized to valsartan had greater odds of being
in the HFiEF group, whereas those with an ischemic pathogenesis or more dilated left ventricle had much lower odds of a
substantial improvement in EF. In addition to these 7 variables,
the following neurohormones were measured in a large subset
of subjects (n=2380): B-type natriuretic peptide, norepinephrine, PRA, aldosterone, high-sensitivity C-reactive protein,
detectable troponin, and level of hs-troponin T. Out of these
variables, only a detectable hs-troponin T at baseline was independently associated with reduced odds of being in the HFiEF
group (OR, 0.43). The median (interquartile range) of probabilities of being in the HFiEF group estimated using a logistic
regression model with the 8 independent correlates were 0.15
(0.08–0.22) in the HFiEF group and 0.06 (0.03–0.10) in the
continued HFrEF group. The area under the receiver operating characteristic curve was 0.76 (95% confidence interval,
0.72–0.79). Thus, these 8 baseline variables provided some
discrimination of subjects who had a substantially improved
EF >12 months of follow-up. However, only 3 subjects had
>50% estimated likelihood of being in the HFiEF group.
Survival
The 3519 subjects who had baseline EF of <35% and a
12-month assessment of EF were followed for a maximum
Discussion
In this Val-HeFT population, 9% of subjects with a baseline
EF of <35% recovered their EF at 12 months. This group of
subjects with HFiEF had a higher prevalence of hypertension,
a lower prevalence of ischemic heart disease, a less severe
hemodynamic, biomarker, and neurohormonal profile, and they
were treated with a more intense HF medication regimen. Subjects who had higher blood pressure and those treated with a
β-blocker or randomized to valsartan had greater odds of being
in the HFiEF group, whereas those with an ischemic pathogenesis, a more dilated left ventricle, and a detectable hs-troponin T
at baseline had much lower odds of a substantial improvement
in EF. Improvement of the EF to >40% was associated with a
better survival compared with persistently reduced EF. Our data
support HFiEF as a stratum of HFrEF with a more favorable outcome, which occurs in a minority of patients with HFrEF who
have a lower prevalence of ischemic heart disease, a less severe
hemodynamic, biomarker, and neurohormonal profile and who
are treated with a more intense HF medication regimen.
In our patient population, only 9% of subjects with a baseline EF of <35% recovered their EF to >40% at 12 months.
This is close to 10% of patients with a baseline EF of <50%,
who recovered their EF to ≥50% in the study by Basuray et
al.3 Our results are consistent with others in that, compared
with HFrEF, subjects with HFiEF are younger,2,3 with a lower
prevalence of coronary artery disease,2 a better renal function,2,3 and a better biomarker and neurohormonal profile.3
In contrast to other reports,2,3 our subjects with HFiEF had a
similar symptom profile compared with subjects with HFrEF
and were more likely to be treated with a β-blocker, an agent
known to improve EF and long-term survival in HFiEF.17 New
in this study are the findings that patients randomized to valsartan treatment had greater odds of being in the HFiEF group.
Our study identified 8 variables that were independent
correlates of HFiEF: male sex, ischemic pathogenesis, body
mass index, diastolic blood pressure, LVIDd/BSA, detectable
hs-troponin T, β-blocker therapy at baseline, and treatment
with valsartan. However, we could not determine why the EF
improved. Although these variables may be useful to predict
which patients are more likely to have improvement in EF, all
the 8 independent correlates combined identified only a few
subjects who had a high probability of improvement in EF.
Their predictive performance needs to be confirmed in other
patient populations.
Our results are consistent with others in that, compared
with HFrEF, subjects with HFiEF have a better long-term
5 Florea et al Heart Failure With Improved Ejection Fraction
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survival.3 Other studies showed better long-term outcomes in
patients with HF who have had an improvement in EF. Cintron
et al18 assessed the prognostic value of serial changes in EF in
patients with chronic HF in the V-HeFT (Vasodilator–Heart
Failure Trial) and found a significant and proportionate relationship between the direction and magnitude of changes in
EF over time and the 1-year mortality. Serial assessments
of left ventricular dimensions and function in the Studies of
Left Ventricular Dysfunction (SOLVD)19 and Australia–New
Zealand Carvedilol Heart Failure20 echocardiographic substudies, the Metoprolol CR/XL Randomized Intervention Trial
in Heart Failure (MERIT-HF) magnetic resonance imaging
substudy,21 and the A-HeFT (African American Heart Failure
Trial)22 have also found an association between favorable
changes in left ventricular dimensions and EF and improved
clinical outcome produced by enalapril, carvedilol, metoprolol, or isosorbide dinitrate and hydralazine combination.
In the study by Cintron et al,18 changes in EF of >5% from
baseline at 6 months (V-HeFT I) and 12 months (V-HeFT
II), irrespective of whether the follow-up EF reached a certain recovery level, were the strongest predictors of survival
and remained significant even after adjustment for therapy
and baseline EF. Although this is perhaps the only study that
addressed and found a consistent proportionality between the
degree of change in the EF and the subsequent change in mortality, it suggests that any substantial improvement in EF is
associated with an improvement in survival.
Several available publications have defined the subset of
patients with HFpEF who previously had HFrEF as heart failure with recovered ejection fraction2,3,17 or heart failure with
better ejection fraction4,23 and have been using different EF
cut-off points for defining this HF category (≥40%,2 ≥45%,17
and ≥50%3,4). In this article, we used the definition of heart
failure with improved ejection fraction with the cut-off point
of >40%, consistent with the current guideline for the management of heart failure.1 We chose to truncate the population by
analyzing only patients whose baseline EF was <35%, rather
than including the entire Val-HeFT population with an EF of
<40% because we wanted to identify a group that clearly had
an improved EF to >40%. Given the error in measurement of
EF, we felt a clear improvement in EF should be at least 5%.
Strengths and Limitations
We used well-characterized patients in the Val-HeFT trial
where outcomes were adjudicated. In addition, we were able
to examine EF improvement along with several established
prognostic variables, including troponin and N-terminal probrain natriuretic peptide. The use of β-blockers and mineralocorticoid receptor antagonists was lower in the Val-HeFT
population compared with that seen in contemporary clinical
trials as was the absence of cardiac resynchronization therapy
in the Val-HeFT population. Because these therapies strongly
affect reverse remodeling and recovery of systolic function,
these might influence the proportion of patients with improved
EF and the overall impact of our results. In addition, we were
not able to present the data on whether the patients who entered
this study were on target doses of β-blockers or angiotensinconverting enzyme inhibitors and for how long. Although we
found only 9% of patients with a baseline EF of <35% who
had a 12-month EF of >40%, this probably underestimated the
true proportion of patients with systolic dysfunction who got
to the recovered state because the patients who entered this
study have already been on optimal HF therapy. When individuals are recruited into new trials while on background therapy
and there is an EF eligibility criterion, eligible patients will
predominantly be nonresponders to standard therapy and with
a poor prognosis. Thus, the patients entered into the new trials
may not be adequately representative of HF seen in clinical
practice. Val-HeFT enrolled patients with an EF of <40%. We
excluded ≈12% of the Val-HeFT subjects who did not have a
baseline EF of <35% and ≈18% who did not have a 12-month
EF. Thus, our findings do not represent the entire Val-HeFT
cohort. Although we report several state-of-practice statistical
indices for evaluating prediction models, the individual predicted probabilities and predicted event-free survival curves
that are most directly applicable to clinical practice ignore the
uncertainty in the estimates as is often done when prediction
models are used in clinical practice.
Conclusions
In this sample of patients with chronic HF, a minority of subjects with a baseline EF of <35% improved their EF to >40%
at 12 months. This group of subjects with HFiEF had a higher
prevalence of hypertension, a lower prevalence of ischemic
heart disease, a less severe hemodynamic, biomarker, and neurohormonal profile, and they were treated with a more intense
HF medication regimen. Subjects who had higher blood pressure and those treated with a β-blocker or randomized to valsartan had greater odds of being in the HFiEF group, whereas
those with an ischemic pathogenesis, a more dilated left ventricle, and a detectable hs-troponin T at baseline had much
lower odds of a substantial improvement in EF. Improvement
in the EF was associated with a better survival compared with
persistently reduced EF. Our data support HFiEF as a stratum
of HFrEF with a less severe hemodynamic, biomarker, and
neurohormonal profile, who are treated with a more intense
HF medication regimen, and who experience a more favorable change in LV function and long-term survival. However,
additional studies are needed to determine whether HFiEF
represents enduring recovery or a separate HF clinical entity
that could be treated differently.
Sources of Funding
Novartis sponsored the Valsartan Heart Failure Trial (Val-HeFT).
Dr Rector was supported by Veterans Health Administration Health
Services Research and Development Grant HFP-98-001.
Disclosures
Drs Anand and Cohn received research grants and honoraria from
Novartis. The other authors report no conflicts.
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CLINICAL PERSPECTIVE
Current guidelines for the management of heart failure (HF) divide patients with HF into 2 categories: those with reduced ejection fraction (EF of ≤40%) and those with preserved EF (>40%; HFpEF). It has been recognized that a subset of patients with
HFpEF previously had heart failure with reduced ejection fraction. These patients with recovery or improvement in EF may be
clinically distinct from those with persistently preserved or reduced EF. The authors performed a post hoc analysis of the 5010
subjects enrolled in the Valsartan Heart Failure Trial (Val-HeFT) and identified 3519 subjects who had echocardiographic
assessment of EF at both baseline and 12-month follow-up. In this sample of patients with chronic HF, a minority of subjects
(9%) with a baseline EF of <35% improved their EF to >40% at 12 months. This group of subjects with HF with improved EF
had a higher prevalence of hypertension, a lower prevalence of ischemic heart disease, a less severe hemodynamic, biomarker,
and neurohormonal profile, and they were treated with a more intense HF medication regimen. Improvement in EF was associated with a better survival compared with persistently reduced EF. The authors propose HF with improved ejection fraction
as a stratum of HF with reduced ejection fraction with a less severe hemodynamic, biomarker, and neurohormonal profile,
who are treated with a more intense HF medication regimen, and who experience a more favorable change in LV function and
long-term survival. Additional studies are needed to determine whether HF with improved ejection fraction represents enduring recovery or a separate HF clinical entity that could be treated differently.
Heart Failure With Improved Ejection Fraction: Clinical Characteristics, Correlates of
Recovery, and Survival: Results From the Valsartan Heart Failure Trial
Viorel G. Florea, Thomas S. Rector, Inder S. Anand and Jay N. Cohn
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Circ Heart Fail. 2016;9:
doi: 10.1161/CIRCHEARTFAILURE.116.003123
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