Download Baseline characteristics of patients with heart failure and preserved

Archives of Cardiovascular Disease (2014) 107, 112—121
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CLINICAL RESEARCH
Baseline characteristics of patients with
heart failure and preserved ejection
fraction included in the Karolinska Rennes
(KaRen) study
Caractéristiques à l’inclusion des patients insuffisants cardiaques
à fraction d’éjection préservée inclus dans l’étude Ka
(Karolinska) Ren (Rennes)
Erwan Donal a,b,i,∗, Lars H. Lund c,i, Emmanuel Oger d,i,
Camilla Hage c,i, Hans Persson e,i, Amélie Reynaud b,i,
Pierre-Vladimir Ennezat f,i, Fabrice Bauer g,i,
Catherine Sportouch-Dukhan h,i, Élodie Drouet h,i,
Jean-Claude Daubert a,b,i, Cecilia Linde c,i , On behalf
of the KaRen Investigators
a
Département de Cardiologie & CIC-IT U 804, Hôpital Pontchaillou, CHU de Rennes, rue
Henri-Le-Guillou, 35000 Rennes, France
b
LTSI, Université Rennes 1, INSERM 1099, Rennes, France
c
Department of Medicine, Karolinska Institutet and Department of Cardiology, Karolinska
University Hospital, Stockholm, Sweden
d
Clinical Investigation Center INSERM CIC-0203, CHU de Rennes, Rennes, France
e
Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Stockholm,
Sweden
f
Service de Cardiologie, CHU de Lille, Lille, France
g
Département de Cardiologie, CHU de Rouen, Rouen, France
h
Département de Cardiologie, CHU de Montpellier, Montpellier, France
i
Société française de cardiologie, Paris, France
Received 19 September 2013; received in revised form 2 November 2013; accepted 18 November
2013
Available online 30 December 2013
∗ Corresponding author. Département de Cardiologie & CIC-IT U 804, Hôpital Pontchaillou, CHU de Rennes, rue Henri-Le-Guillou, 35000
Rennes, France.
E-mail addresses: [email protected], [email protected] (E. Donal).
1875-2136/$ — see front matter © 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.acvd.2013.11.002
Baseline characteristics of patients in KaRen
KEYWORDS
Heart failure with
preserved ejection
fraction;
Registry;
Clinical
characteristics;
Echocardiographic
characteristics
MOTS CLÉS
Insuffisance
cardiaque à fraction
d’éjection
préservée ;
Registre ;
Caractéristiques
cliniques ;
Échocardiographie
113
Summary
Background. — Karolinska Rennes (KaRen) is a prospective observational study to characterize
heart failure patients with preserved ejection fraction (HFpEF) and to identify prognostic factors
for long-term mortality and morbidity.
Aims. — To report characteristics and echocardiography at entry and after 4—8 weeks of followup.
Methods. — Patients were included following an acute heart failure presentation with B-type
natriuretic peptide (BNP) > 100 ng/L or N-terminal pro-BNP (NT-proBNP) > 300 ng/L and left ventricular ejection fraction (LVEF) > 45%.
Results. — The mean ± SD age of 539 included patients was 77 ± 9 years and 56% were women.
Patient history included hypertension (78%), atrial tachyarrhythmia (44%), prior heart failure
(40%) and anemia (37%), but left bundle branch block was rare (3.8%). Median NT-proBNP was
2448 ng/L (n = 438), and median BNP 429 ng/L (n = 101). Overall, 101 patients did not return
for the follow-up visit, including 13 patients who died (2.4%). Apart from older age (80 ± 9
vs. 76 ± 9 years; P = 0.006), there were no significant differences in baseline characteristics
between patients who did and did not return for follow-up. Mean LVEF was lower at entry than
follow-up (56% vs. 62%; P < 0.001). At follow-up, mean E/e was 12.9 ± 6.1, left atrial volume
index 49.4 ± 17.8 mL/m2 . Mean global left ventricular longitudinal strain was −14.6 ± 3.9%; LV
mass index was 126.6 ± 36.2 g/m2 .
Conclusions. — Patients in KaRen were old with slight female dominance and hypertension as
the most prevalent etiological factor. LVEF was preserved, but with increased LV mass and
depressed LV diastolic and longitudinal systolic functions. Few patients had signs of electrical
dyssynchrony (ClinicalTrials.gov.— NCT00774709).
© 2014 Elsevier Masson SAS. All rights reserved.
Résumé
Contexte. — Karolinska Rennes (KaRen) est une étude observationnelle prospective menée afin
de caractériser une cohorte de patients insuffisants cardiaques à fraction d’éjection préservée
et afin d’identifier des facteurs pronostiques de morbi-mortalité.
Objectif. — Nous rapportons ici, les caractéristiques à l’inclusion et à la visite de 4—8 semaines,
incluant les données échocardiographiques analysées au centre de relecture.
Méthodes. — Les patients sont inclus suite à une hospitalisation urgente pour une insuffisance
cardiaque clinique. Les natriurétique peptide de type B (BNP) > 100 ng/L or N-terminal proBNP (NT-proBNP) > 300 ng/L et la fraction d’éjection du ventricule gauche > 45 % étaient des
pré-requis à l’inclusion dans l’étude.
Résultats. — Parmi les 539 patients inclus, l’âge était de 77 ± 9 ans avec 56 % de femmes. Les
patients étaient très fréquemment hypertendus (78 %), avec une histoire d’arythmie atriale
(44 %), l’insuffisance cardiaque avant (40 %) et l’anémie (37 %), mais la prévalence du bloc de
branche gauche était limitée (3,8 %). Le NT-proBNP médian était de 2448 ng/L (n = 438) et le BNP
médian 429 ng/L (n = 101). Sur l’ensemble, 101 patients ne sont pas revenus à la visite de suivie
dont 13 (2,4 %) qui sont décédés. Outre l’âge plus avancé (80 ± 9 vs 76 ± 9 années ; p = 0,006)
il n’y a avait aucune différence dans les caractéristiques des patients vus en urgence puis à
la visite de 4—8 semaines. La fraction d’éjection du ventricule gauche était plus basse lors de
l’admission en urgence qu’à la visite de 4—8 semaines (56 % vs 62 % ; p < 0,001). À 4—8 semaines,
le rapport E/e était de 12,9 ± 6,1, le volume de l’oreillette gauche de 49,4 ± 17,8 mL/m2 .
Le strain global longitudinal était de −14,6 ± 3,9 % et a masse ventriculaire gauche était de
126,6 ± 36,2 g/m2 .
Conclusions. — Les patients inclus dans KaRen sont surtout des femmes âgées et hypertendues.
La fraction d’éjection du ventricule gauche est préservée avec une augmentation de la masse
ventriculaire, une altération de la fonction diastolique et de la composante longitudinale
de la fonction systolique. L’asynchronisme électrique est peu fréquent (ClinicalTrials.gov.—
NCT00774709).
© 2014 Elsevier Masson SAS. Tous droits réservés.
Introduction
In recent years, heart failure with preserved ejection
fraction (HFpEF) has been increasingly recognized as a
pathophysiological entity [1]. The proportion of patients
with heart failure with HFpEF is about 50% of the general heart failure population [2—4]. In epidemiological
surveys, the prognosis of HFpEF is nearly as poor as for
114
heart failure with reduced ejection fraction (HFrEF) [5—8].
Despite extensive efforts to characterize HFpEF [9] and several randomized therapeutic trials, little is known about
the clinical course and treatment options for this condition.
Guidelines are therefore still restricted to modifying the risk
factors predominant in HFpEF, such as to obtain strict control of blood pressure or to treat symptoms of congestion
with diuretics [10].
Current guidelines highlight the importance of additional
objective criteria to signs and symptoms and preserved or
normal ejection fraction for the diagnosis of HFpEF [9—11].
These criteria include normal left ventricular volume,
increased left atrial volume, left ventricular hypertrophy and/or diastolic dysfunction and natriuretic peptides
[12], whereas diagnostic criteria for dyssynchrony are not
included. Little is known about the role of electrical
and mechanical dyssynchrony in HFpEF [13,14]. A typical
left bundle branch block (LBBB) was found in 14.4% of
patients included in CHARM-Preserved [15] and 8.1% in IPRESERVE [16]. In ischemic HFpEF, it has been demonstrated
that both left ventricular diastolic and atrial mechanical
dyssynchrony may impair diastolic function [17]. It has
therefore been suggested that dyssynchrony may contribute
to the pathophysiology of HFpEF, warranting the need for
a prospective study to analyse the importance of these
factors [17,18].
To further characterize HFpEF patients and to look for
new therapeutic options in these patients, we conducted a
prospective registry study of HFpEF patients admitted for an
acute heart failure exacerbation in Sweden and France — the
Karolinska Rennes (KaRen) study [19]. The aim of this report
is to describe and compare the clinical and basic echocardiographic characteristics of the study populations at acute
presentation and at 4—8-week follow-up.
Methods
The rationale and design of the KaRen study have previously
been published [19]. Briefly, KaRen is a prospective, multicentre, international, observational study with the primary
objective to determine whether electrical or mechanical dyssynchrony independently affects the prognosis. The
present work sought to characterize the HFpEF patients
included in KaRen according to their main clinical, electrocardiographic (ECG) and echocardiographic characteristics.
Patients were included in KaRen between 1 May 2007 and
1 December 2011 in 10 French and three Swedish university hospitals. Details on inclusion and exclusion criteria
have been published [19]. Patients were recruited consecutively as far as was possible. We aimed to identify
at least 400 patients seeking medical attention in the
emergency department with clinical signs and symptoms
of heart failure according to the Framingham criteria
[13]. A left ventricular ejection fraction (LVEF) ≥ 45% by
echocardiography and natriuretic peptides (B-type natriuretic peptide [BNP] > 100 ng/L or N-terminal pro-BNP
[NT-proBNP] > 300 ng/L) were also required. All three inclusion criteria (clinical heart failure, LVEF and peptides) had
to be verified within 72 hours of presentation.
Anemia was defined as hemoglobin < 120 g/L in women
and < 130 g/L in men, and renal dysfunction as serum
E. Donal et al.
creatinine > 120 ␮mol/L or an estimated glomerular filtration rate (eGFR) < 60 mL/min. Coronary artery disease was
defined as a history of acute myocardial infarction, coronary
artery bypass or angioplasty or > 50% coronary artery stenosis on a coronary angiogram. Clinical heart failure signs were
classified as signs of left heart failure, right heart failure or
both [19].
Patients who presented acutely with heart failure were
screened, and patients were included based on inclusion
criteria in the acute state including conventional assessment of ejection fraction, but with no detailed analysis
of other parameters. Patients returned to a stable state
(with or without hospitalization) according to the conventional treatment decided by individual investigators. After
4—8 weeks, included patients returned to the hospital for
exhaustive clinical, ECG and biological reassessment and a
detailed echocardiographic study. These half-day visits were
stringently analysed in dedicated core centres. Follow-up
was continued for ≥ 18 months.
In this report, we describe the clinical and basic
echocardiographic characteristics of patients in KaRen at
baseline and at 4—8-week follow-up. The description is
based on cut-off values published in 2007 in a consensus paper about HFpEF [9] and according to the American
Society of Echocardiography (ASE)/European Association
of Echocardiography (EAE) recommendations for chamber
quantification in echocardiography [20].
Statistical analysis
Continuous variables are presented as means ± standard
deviations (SDs) and/or medians (interquartile ranges
[IQR]). Categorical variables are presented as counts and
percentages.
To compare the means of measurements performed at
two time points (baseline and 4—8 weeks), we used Student’s
t test to produce a statistic for the null hypothesis that the
mean difference equals zero. All P-values are two-sided and
statistical significance was set at 0.05. All analyses were performed using SAS® 9.3 Statistical Procedures (SAS Institute
Inc., Cary, NC, USA).
Results
The flow chart of the KaRen study is shown on Fig. 1. Patients
(n = 584) were considered for inclusion in KaRen between
1 May 2007 and 1 December 2011. Of these, 29 did not
meet inclusion criteria and 16 withdrew consent. Thus, 539
patients were enrolled in the study and assessed at baseline. Of these, 470 patients were admitted to hospital for
heart failure treatment and 69 were sent home after treatment revision. Thirteen patients (2.4%) died and 21 (3.9%)
were re-hospitalised for heart failure between enrolment
and the 4—8-week visit. A total of 101 patients did not
return for the 4—8-week follow-up visit, leaving 438 who
were re-assessed at the 4—8-week visit. Apart from older
mean age (80 ± 9 vs. 76 ± 9 years; P = 0.006), there were no
statistically significant differences in baseline characteristics between patients who returned for the follow-up visit
and those who did not.
Baseline characteristics of patients in KaRen
Figure 1.
115
Flow chart of the study from enrolment to 4—8-week follow-up.
Characteristics at acute admission and
4—8 weeks
The mean age of the 539 patients was 77 ± 9 years, and
56% were women (Table 1). A history of heart failure was
found in 40%. The history of heart failure symptoms revealed
that 80% of patients had been New York Heart Association
(NYHA) class I/II before the exacerbation of acute heart
failure, but at admission, most patients (90%) were NYHA
III/IV. Mean LVEF at admission was 56 ± 7%, and 303 (56%)
had LVEF > 55%. At admission, 456 patients (85%) had ≥ two
major and 83 (15%) had one major and ≥ two minor Framingham criteria for heart failure. Median NT-proBNP was
2448 ng/L and median BNP 439 was 429 ng/L (Table 1). Mean
systolic blood pressure was 150 ± 31 mmHg and median [IQR]
heart rate was 80 [68—100] bpm. The median [IQR] eGFR was
61 [43—76] mL/min. Among the 470 hospitalized patients,
the mean length of hospital stay at the acute heart failure
admission was 5 days (range 0—58 days). The distributions
of Framingham criteria of heart failure at index hospitalization and at 4—8-week follow-up are shown on Fig. 2.
Many patients still had clinical symptoms or signs of heart
failure at the 4—8-week visit, e.g. 30% of the population
still had peripheral oedema despite 4—8 weeks of dedicated
treatments.
Figure 2. Distribution of major and minor Framingham criteria
for heart failure at admission to the hospital and in a stable state
at 4—8-week follow-up.
ECG and echocardiographic measurements at
4—8 weeks
at baseline than at the 4—8-week visit (56 ± 7% vs. 62 ± 7%;
P < 0.001). Left ventricular fractional shortening was > 30%
for most patients (207/356; 61%). Left ventricular s’
was > 7 cm/s for 105/356 (30%). Left ventricular global longitudinal strain (GLS) was < −16% for 139/356 (67%).
ECG
Left ventricular volumes
At 4—8 weeks, 244 were classified as ‘‘no atrial arrhythmia’’ out of 378 (64.55%). Conduction disturbances were
rare among these patients, with only 28 out of 244 (11.48%),
13.5% having a long PR interval (> 200 ms) and 52 out of 348
not V-paced patients (14.94%) having a QRS width > 120 ms
(Table 1). Right bundle branch block (RBBB) was present in
31 out of 348 (8.91%) and LBBB in 24 out of 348 (6.90%).
A total of 218/356 patients (63%) had a left ventricular
end-diastolic volume ≤ 97 mL/m2 , showing no significant left
ventricular enlargement [9].
Left ventricular ejection fraction
Table 2 contains echocardiographic characteristics at
4—8 weeks. LVEF was preserved, but was significantly lower
Diastolic function
Fig. 3 highlights the importance of diastolic dysfunction
and the association of enlarged left atrium and persistent E/e > 12 at 4—8 weeks. E/e > 15 was only found at the
4—8-week visit for 94/356 patients (28%), but diastolic dysfunction was severe as e’ was < 11 cm/s for 310/356 patients
(88%). Also, left atrial indexed volume was > 32 mL/m2 (a
116
E. Donal et al.
Table 1 Main clinical, biological and ECG characteristics at admission for acute heart failure and after 4—8 weeks of
conventional therapy in all patients.
At admission
(n = 539)
At 4—8-week visit
(n = 438)
Age (years)
77 ± 9
—
Women
303 (56)
—
Hypertension
419 (78)
—
Prior heart failure
216 (40)
—
Prior stroke
56 (10)
—
Coronary artery disease
158 (29)
—
Prior myocardial infarction
77 (15)
—
Valvular heart disease
74 (14)
—
Diabetes
161 (30)
—
Renal dysfunction
146 (27)
—
Anemia
202 (37)
—
COPD
73 (14)
—
NYHA class
I
II
III
IV
n = 527
4 (0.5)
49 (9.5)
211 (40)
263 (50)
49 (12)
243 (62)
90 (23)
10 (3.0)
Heart failure clinical presentation
Biventricular
Isolated LV
Isolated RV
364 (69)
129 (24)
36 (7.0)
63 (35)
44 (25)
71 (40)
3rd heart sound
31 (6.0)
11 (3.0)
SBP (mmHg)
150 ± 31
138 ± 24
DBP (mmHg)
77 ± 19
73 ± 12
Pulse pressure (mm Hg), median [IQR]
70 [55—90]
65 [50—78]
Heart rate (bpm), median [IQR]
80 [68—100]
68 [60—76]
Weight (kg)
79 ± 20
78 ± 19
BMI (kg/m2 )
29 ± 6
29 ± 6
NT-proBNP (ng/L)a , median [IQR]
2448 [1290—4790]
1409 [517—2635]
b
BNP (ng/L) , median [IQR]
429 [229—805]
277 [136—570]
Hemoglobin (g/L)
123 ± 19
125 ± 17
eGFR (mL/min), median [IQR]
61 [43—76]
60 [42—77]
Atrial arrhythmia
218 (44)
171 (39)
PR interval > 200 ms
26 (11)
25 (14)
QRS duration > 120 ms
69 (15)
57 (16)
LBBB
16 (3.5)
14 (3.8)
RBBB
35 (7.6)
24 (6.6)
Paced V rhythm
35 (7.1)
29 (7.3)
Data are mean ± standard deviation or n (%) unless otherwise specified. IQR: interquartile range; BMI: body mass index; BNP: B-type
natriuretic peptide; COPD: chronic obstructive pulmonary disease; DBP: diastolic blood pressure; ECG: electrocardiogram; eGFR:
estimated glomerular filtration rate; LBBB: left bundle branch block; LV: left ventricular; NT-proBNP: or N-terminal pro-B-type
natriuretic peptide; NYHA: New York Heart Association; RBBB: right bundle branch block; RV: right ventricular; SBP: systolic blood
pressure.
a n = 434.
b n = 101.
Baseline characteristics of patients in KaRen
Table 2
117
Echocardiographic characteristics.
4—8-week visit
(n = 356)
Mean ± SD
LVEF (%)
LVEDV (mL/m2 )
LVESV (mL/m2 )
LA volume (mL/m2 )
Inter-ventricular septal thickness (mm)
LV end-diastolic diameter (mm)
LV end-systolic diameter (mm)
LV fractional shortening (%)
LV mass indexed (g/m2 )
Stroke volume (mL/m2 )
LA diameter (mm)
Indexed LA volume (mL/m2 )
RA area (cm2 )
Cardiac output (mL/m2 )
Tricuspid regurgitation (m/s)
E-wave deceleration time (ms)
E/A
Mitral inflow duration/RR interval (%)
e (cm/s) (average septal an lateral part of mitral annulus)
E/e
LVPEI (ms)
Inter V time delay (ms)
LV s (cm/s) (average septal and lateral side of mitral annulus)
Time difference between s septal and lateral side of mitral
annulus (ms)
Delay between longitudinal strain peaks from the lateral and
the septal LV walls (ms)
Global longitudinal strain (%)
RV fractional shortening (%)
TAPSE (mm)
RV s (cm/s)
RV strain (%)
62
92
35
49
11.6
47.3
32.1
32.7
126.6
31
45.5
49.4
20.5
4.8
2.9
194
1.8
51
7.9
12.9
84
19
7.3
35
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
7
30
15
18
2.3
6.3
6.6
7.9
36.2
8
6.6
17.8
5.9
1.5
0.6
75
1.3
12
2.6
6.1
31
16
2.0
58
18 ± 192
−14.6
19.4
17
11
−19
±
±
±
±
±
3.9
5.6
6
3
5
Median (range)
63
86
33
46
11
47
32
33
123
29
45
46.6
20
4.6
2.8
184
1.2
51
7.5
11.3
79
14
7
19
(45—80)
(33—211)
(8—95)
(4-158)
(6—21)
(26—65)
(12—53)
(12—62)
(40—266)
(4—60)
(23—71)
(14.0—158.2)
(8—55)
(1.6—12.0)
(1.0—4.7)
(54—687)
(0.3—8.3)
(11—57)
(2.5—18.0)
(2.5—40.6)
(5—360)
(0—102)
(3—15)
(−94, 301)
27 (−295, 332)
−15
18.4
17
11
−19
(−25 to —3)
(9.4—39.3)
(4—31)
(3—20)
(−35—27)
LA: left atrial; LV: left ventricular; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESV: left
ventricular end-systolic volume; LVPEI: left ventricular pre-ejection interval; RA: right atrial; RV: right ventricular; SD: standard
deviation; TAPSE; tricuspid annular plane systolic excursion.
predictor of cardiovascular events [9]) for 220/356 patients
(85%).
Left ventricular hypertrophy
Signs of left ventricular hypertrophy were found on ECG in
a minority of patients (25/356; 5%), but echocardiography
showed left ventricular hypertrophy in 39% of patients.
Medication
The prescription rates of angiotensin-converting-enzyme
inhibitors (ACEi)/angiotensin II receptor blockers (ARBs) and
beta-blockers were 60% and 64%, respectively, at admission
and increased by around 10% at discharge (Table 3). The
prescription rate of K+ -sparing diuretics was low, but doubled from 10% to 22% between admission and 4—8-week
follow-up. More than half of the patients (60%) were on
loop diuretics at admission, and this increased to 83% at
4—8 weeks, with a median (range) dose of furosemide at
4—8 of 40 (20—1000) mg/day. Diuretics were discontinued
in 29 patients after enrolment, whereas 43 patients never
received diuretics. Conversely, the prescription rate of calcium antagonists (34% at admission) decreased somewhat
over time. Anti-arrhythmic drugs were used in 15% and did
not increase over time.
Discussion
KaRen prospectively included a population of HFpEF patients
as strictly defined by validated Framingham criteria, preserved ejection fraction and elevated natriuretic peptides.
The short-term mortality was low. The populations at entry
and 4—8-week follow-up were generally similar, except for
lower LVEF at study entry. After 4—8 weeks of dedicated
118
E. Donal et al.
Figure 3. A. Repartition of the individual values of GLS (left) and LV s’ (right) pulsed tissue Doppler values averaged from the measurement
at the mitral annulus septal and lateral sides. B. Repartition of the individual values of TAPSE (left) and RV s’ (center) (pulse tissue Doppler
recorded at the tricuspid annulus, free wall side); and repartition of the tricuspid regurgitation peak velocities (right). Horizontal lines show
median values. GLS: global longitudinal strain; LV: left ventricular; RV; right ventricular; TAPSE; tricuspid annular plane systolic excursion.
treatment, an important proportion of patients still showed
symptoms and signs of heart failure. Aetiological factors
and co-morbid conditions were as previously described for
HFpEF patients [2—5], with a high proportion of female
gender, hypertension and atrial tachyarrhythmias. Diagnostic criteria for HFpEF left ventricular diastolic dysfunction,
according to guideline criteria, were frequently observed,
and left ventricular systolic dysfunctions were frequently
found despite LVEF > 45%. Also, dyssynchrony as classically
defined by bundle branch block or atrioventricular conduction abnormalities does not seem to be a strong determinant
in HFpEF.
Table 3 Medication at discharge from acute admission and after 4—8 weeks of conventional therapy in the 438 patients
who attended 4—8-week follow-up.
At admission
(n = 438)
ACEi/ARB
Beta-blockers
Digoxin
Diuretics
K+ -sparing diuretics
Nitrates
Calcium antagonists
Anti-arrhythmic drugs
Antiplatelets
Warfarin
264
284
31
264
45
17
152
68
179
179
(60)
(64)
(7)
(60)
(10)
(4)
(34)
(15)
(41)
(40)
At discharge
(n = 438)
313
319
40
378
64
24
133
89
167
228
ACEi: angiotensin-converting-enzyme inhibitor; ARB: angiotensin II receptor blocker.
(73)
(74)
(9)
(88)
(15)
(6)
(31)
(18)
(39)
(53)
4—8 weeks
(n = 438)
296
293
33
361
97
15
119
67
142
222
(68)
(80)
(8)
(82)
(22)
(3)
(28)
(15)
(33)
(51)
Baseline characteristics of patients in KaRen
Baseline characteristics in KaRen and clinical
presentation
The KaRen patients diagnosed with HFpEF are different from patients with HFrEF, with a rather high female
representation, high mean weight and a high proportion
of underlying hypertension. The mean LVEF at admission
(56%) was comparable to patients in the OPTIMIZE-HF registry [21], but KaRen patients more often had a history
of atrial fibrillation [22]. Mean age was high (77 ± 9 years)
and underlying diabetes, coronary artery disease and COPD
were reported less often than in most previous studies
[15—17,22]. Patients included in KaRen are thus slightly different from patients previously described, mainly in the
United States of America. Only 40% of KaRen patients had a
prior heart failure admission, which is much lower than in
registries such as ADHERE [23] (63%) and CHARM-Preserved
[24] (69%) and may reflect the unselective nature of our
study. This may in part also account for the low shortterm mortality. The patient profile in KaRen was driven
by the fact that patients were admitted only in large
hospitals and their dominant symptoms were linked to
heart failure. They were admitted and examined in cardiology units. The mean blood pressure of 150/77 mmHg
in KaRen is comparable to ADHERE [23] (152/79 mmHg).
In KaRen and ADHERE, patients were included after an
acute decompensation (main diagnosis). In OPTIMIZE-HF,
blood pressure was lower (129/72 mmHg), but patients were
recruited according to whether they had signs or symptoms of heart failure as a primary discharge diagnosis
[14,25,26].
There are several characteristics and clinical presentations of HFpEF that are not necessarily different from HFrEF.
In spite of different baseline characteristics, the acute clinical presentation in KaRen was similar to HFpEF and HFrEF
patients [22,26]. As in the OPTMIZE-HF registry [14], 69%
of patients presented with signs of left ventricular and
right ventricular failure and only 24% presented with isolated left ventricular failure. Definitively, it is not possible
to distinguish HFrEF and HFpEF patients based on clinical
presentation alone [14,15].
It is known that about 50% of patients with HFrEF or
HFpEF are discharged from hospital with residual signs
of congestion [27]. We did not measure body weight at
the time of discharge. However, weight was only reduced
by a mean of 1 kg at the 4—8-week follow-up compared
to hospital admission, suggesting insufficient treatment of
congestion at the acute admission in spite of a mean hospital stay of 5 days and relatively high usage of diuretics.
More evidence for insufficient therapy is the fact the NTproBNP and BNP levels remained high even at 4—8 weeks.
It is natural to assume that one of the reasons for this
insufficient improvement is a lack of guideline-indicated
treatments besides diuretics and drugs for hypertension
[10]. However, this is not the only reason since HFrEF
patients, despite guidelines for highly beneficial treatment,
have the same proportion of insufficient improvements
[27]. According to the treatments prescribed in patients
included in KaRen, beta-blockers, diuretics, aldosterone
antagonists and other blockers of the renin angiotensin
system were prescribed in similar proportions to previous
reports [28].
119
Echocardiographic characteristics
Left ventricular ejection fraction > 45% does not mean that
there is no anatomic or functional reason to develop signs
and symptoms or heart failure [14,29]. Most patients had
left ventricular concentric remodelling or increase in left
ventricular mass with an abnormal left ventricular longitudinal function (left ventricular: LV-s’ 7.3 ± 2.0 cm/s or
GLS — 14.6 ± 3.9%). These patients had also diastolic dysfunction (depressed e’ 7.9 ± 2.6 cm/s and large left atrium).
Still, after 4—8 weeks of dedicated treatment, a large number of patients kept the association E/e > 12 and enlarged
left atrium (Fig. 3). However, these abnormalities of the
systolic and diastolic functions of the left heart were not
observed in every patient. In I-PRESERVE, the left atrium
was normal in 34% of the population and diastolic function was classified as normal in 31% [29]. These left heart
dysfunctions are frequently associated with right heart
abnormalities that might also be more obvious than any
left heart remodelling [30]. The right heart longitudinal
function is frequently depressed (RV s 11 ± 3 cm/s; RV
longitudinal strain—19 ± 5%, TAPSE 17 ± 6 mm) and the estimated pulmonary pressure after 4—8 weeks of treatment
of the congestion remains high in many patients (tricuspid
regurgitation 2.9 ± 0.6 m/s). The prevalence of electrical
and mechanical dyssynchrony was low (LBBB 3.8%). Nevertheless, new sophisticated and, very probably, more
appropriate tools to characterize mechanical dyssynchrony
(like strain peaks dispersion) should very probably be looked
for in this population [31]. Also, it would be relevant to
measure the strain delay index, which has been elegantly
demonstrated as clearly abnormal in 38 patients with HFpEF
[32]. Further work is thus required before affirming that
the majority of patients included in KaRen have no significant mechanical dyssynchrony that might affect myocardial
function efficiency and prognosis.
Limitations
The present report is limited to the assessment of HFpEF
patients during two phases of their disease: at admission for
acute decompensation and 4—8 weeks later after treatment
optimization. A complete and analysable echocardiographic
recording was unfortunately only available for 356/539
patients (66%). Despite informed consent at baseline, these
76 did not return to the hospital for their scheduled 4—8week visit. They all explained that they felt too old and
dependent to justify any further displacement to the hospital. It was evident that many HFpEF patients did not
complain between acute episodes despite the presence of
signs and symptoms. They were considering their health
status as mainly linked to their age. A comparison of the
characteristics of patients who had an echocardiography
versus those who did not showed any difference. The baseline echocardiography had to be performed within the first
72 hours after admission, but did not have to be digitally
recorded and complete; it was just to assess LVEF. Only
the 4—8-week echocardiography had to be fully digitally
recorded and re-interpreted at the core laboratory for
echocardiography. The current guidelines define LVEF ≥ 50%
as abnormal [10]. In KaRen, LVEF was 45—49% for 15% of the
120
E. Donal et al.
population, the others have as required by current guidelines, a LV EF ≥ 50%.
[5]
Conclusions
Patients in KaRen were old with slight female dominance,
a high rate of hypertension and much co-morbidity. LVEF
was preserved despite depressed left ventricular longitudinal and diastolic functions. Electric dyssynchrony does not
seem to be a strong determinant in HFpEF. After 4—8 weeks
of dedicated treatment, an important proportion of patients
still showed symptoms and signs of heart failure.
Disclosure of interest
The study was partly supported by grants from Fédération
française de cardiologie/Société française de cardiologie,
France and Medtronic Bakken Research Center, Maastricht,
The Netherlands. In regard to the KaRen study, we received
a grant from Medtronic Europe.
[6]
[7]
[8]
[9]
[10]
Acknowledgements
We would like to thank the following people: investigators
in France: Christophe Leclercq, CHU de Rennes; Pascal de
Groote and Pierre-Vladimir Ennezat, CHU de Lille; Stéphane
Lafitte and Patrica Réant, CHU de Bordeaux; Fabrice Bauer,
CHU de Rouen; Genevieve Derumeaux and Cyrille Bergerot,
CHU de Lyon; Christian de Place, CHU de Rennes; Yves
Juilliere and Christine Selton-Suty, CHU de Nancy; Damien
Logeart, Hôpital Lariboisière, Paris; Pascal Gueret and Pascal Lim, Hôpital Henri-Mondor, Créteil; Jean-Noel Trochu
and Nicolas Pirou, CHU de Nantes; Gilbert Habib, Hôpital La
Timone, Marseille; Francois Tournoux, Hôpital Lariboisière,
Paris.
Research nurses in France: Marie Guinoiseau, Valerie Le
Moal Rennes University Hospital.
Investigators in Sweden: Ida Haugen-Löfman, Karolinska
university hospital; Magnus Edner, Karolinska university hospital; Hans Emtell, Danderyd Hospital.
French Society of Cardiology: department of registries:
Nicolas Danchin, Genevieve Mulak, Elodie Drouet and
Hakeem F. Admane.
[11]
[12]
[13]
[14]
[15]
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