International Journal of Cardiology 307 (2020) 119–124

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Validation of the Larissa Heart Failure Risk Score for risk stratification in
acute heart failure
Takeshi Kitai a,⁎,1,2, Andrew Xanthopoulos b,1,2, W.H. Wilson Tang j,2, Shuichiro Kaji a,2, Yutaka Furukawa a,2,
Shogo Oishi c,2, Eiichi Akiyama d,2, Satoshi Suzuki e,2, Masayoshi Yamamoto f,2, Keisuke Kida g,2,
Takahiro Okumura h,2, John Skoularigis b,2, Filippos Triposkiadis b,2, Yuya Matsue i,2
a
Departments of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
b
Department of Cardiovascular Medicine, University General Hospital of Larissa, Larissa, Greece
c
Department of Cardiology, Himeji Cardiovascular Center, Himeji, Japan
d
Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan
e
Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
f
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
g
Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan
h
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
i
Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
j
Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background: The LHFRS is a simple score derived from three factors (history of hypertension, history of coronary
Received 9 November 2019 artery disease/myocardial infarction, and red blood cell distribution width) deployed for the risk stratification of
Received in revised form 12 December 2019 AHF in Greek population. This study aimed to validate the Larissa Heart Failure Risk Score (LHFRS) in patients
Accepted 27 December 2019 with acute heart failure (AHF) in a Japanese population.
Available online 28 December 2019
Methods: We performed post-hoc analysis of 1670 consecutive patients enrolled in the REALITY-AHF. In all, 964
patients were finally enrolled. Exclusion criteria included patients with anemia, malignancies and sepsis. The pri-
Keywords:
Larissa Heart Failure Risk Score
mary outcome was defined as a composite of all-cause mortality and/or heart failure readmission, and the sec-
Prognosis ondary outcome was defined as all-cause mortality.
Acute heart failure Results: The median admission LHFRS value was 1 (interquartile range [IQR]: 0–2). During a median follow-up of
365 (IQR: 161–365) days, the primary and secondary outcomes were observed in 321 and 157 patients, respec-
tively. LHFRS was an independent predictor of both the primary (adjusted hazard ratio per 1-point increase, 95%
confidence interval: 1.17 [1.04–1.32], p = 0.011), and the secondary outcomes (1.31 [1.12–1.55], p = 0.001). Pa-
tients with higher LHFRS scores (≥2) exhibited significantly worse outcomes than those with lower scores (b2)
both for the primary outcome (1.40 [1.07–1.83], p = 0.014) and the secondary outcome (1.60 [1.09–2.34], p =
0.015). Additionally, LHFRS revealed an excellent goodness of fit (observed versus predicted outcomes) for
predicting both the primary and the secondary outcomes (p N 0.99 and p = 0.99, respectively).
Conclusion: The simple LHFRS was proved as a reliable predictor of outcomes in patients with AHF.
© 2019 Elsevier B.V. All rights reserved.

1. Introduction
Heart failure (HF) is a global pandemic accompanied by high preva-
lence and incidence, especially in the elderly [1]. Japan exhibits a higher
proportion of elderly people worldwide, whereas the number of
⁎ Corresponding author at: Department of Cardiovascular Medicine, Kobe City Medical
Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan.
E-mail address: t-kitai@kcho.jp (T. Kitai).
1
Authors contributed equally.
2
These authors take responsibility for all aspects of the reliability and freedom from bias
of the data presented and their discussed interpretation.
Japanese outpatients with left ventricular (LV) dysfunction has been re-
ported to be 979,000 (0.8% of the total population) and it is projected to
reach 1.3 million by 2030 [2]. Despite improvements in the diagnosis
and treatment of HF, the mortality and rehospitalization rates remain
unacceptably high globally and Japan is no exception [3]. For example,
a pooled analysis including 9075 patients from three Japanese large-
scale, prospective, hospital-based acute HF (AHF) registries revealed a
1-year all-cause mortality of 18.4–22.2% and a 1-year HF readmission
rate ranging from 24.4 to 27.1% [3].
Timely and accurate risk stratification of patients with HF is impor-
tant in terms of providing personalized care, especially in those hospi-
talized for AHF. As a result, a number of predictive scores have been

https://doi.org/10.1016/j.ijcard.2019.12.051
0167-5273/© 2019 Elsevier B.V. All rights reserved.
120 T. Kitai et al. / International Journal of Cardiology 307 (2020) 119–124
developed and validated in AHF [4]. However, in most of these prognos-
tic models, multiple parameters (multivariate risk scores) are included
which makes their calculation challenging, usually requiring the use of
sophisticated calculators [5]. The Larissa Heart Failure Risk Score
(LHFRS) is a simple score derived from three factors (history of hyper-
tension [yes = 0, no = 2]; history of coronary artery disease/myocardial
infarction [yes = 1, no = 0]; and red blood cell distribution width
[RDW] ≥ 15% [yes = 1, no = 0]; best = 0, worst = 4). It was employed
in the early risk stratification of patients with AHF with encouraging
preliminary results in a Greek population [6]; however, it is yet to be
validated in an external cohort. It is well known that heart failure out-
comes and treatment differ between Caucasians and Asians [3,7], and
whether the risk score for patients with HF derived from one race can
retain its value in another race is unclear. Therefore, we tested whether
the LHFRS will also accurately risk stratify Japanese patients enrolled in
the Registry Focused on Very Early Presentation and Treatment in Emer-
gency Department of AHF (REALITY-AHF).
2. Methods
2.1. Study population
The REALITY-AHF study was designed to determine the prognostic
impact of time-to-treatment for AHF performed in the very acute
phase in the emergency department. The study design and primary re-
sults have been reported elsewhere in detail [8–10]. In brief, patients
were included if they were aged ≥20 years and diagnosed with AHF in
the emergency department (ED) within 3 h of their first evaluation by
caregivers. Only the first hospitalization during the study period was
registered and the AHF diagnosis was made based on Framingham
criteria. Exclusion criteria were: 1) treatment with an intravenous (IV)
drug before ED arrival; 2) previous heart transplantation; 3) on either
chronic peritoneal dialysis or hemodialysis; 4) acute myocarditis; and
5) acute coronary syndrome requiring emergent or urgent revasculari-
zation. Among screened patients, 964 patients satisfied the inclusion/
exclusion criteria in the study that performed the initial validation of
the LHFRS [6]. In accordance with the initial evaluation conducted in
Greece, patients were excluded if they had an admission hemoglobin
level b 10 g/dL, malignancy, or sepsis. The evaluation of the patients at
admission included clinical assessment, laboratory blood tests, and
echocardiography. RDW was calculated as: (standard deviation of
mean corpuscular volume divided by mean corpuscular volume) × 100.
The study complied with the 1975 Declaration of Helsinki, and an Insti-
tutional Review Board (IRB) approval was obtained in each participat-
ing center.
2.2. Outcomes
The primary outcome of interest was a combined endpoint of HF re-
admission and all-cause mortality within 1-year after discharge. The
secondary outcome was defined as all-cause mortality within 1-year
after discharge. The first occurrence of readmission or death after dis-
charge was regarded as the outcome date.
2.3. Statistical analysis
Categorical variables are shown as numbers and percentages. Con-
tinuous variables are expressed as mean and standard deviation or me-
dian and interquartile range (IQR) where appropriate. The relationship
between groups and baseline characteristics were tested using the one-
way analysis of variance, Kruskal-Wallis, or Chi-squared tests, where
appropriate. When necessary, variables were transformed for further
analysis. The predictive value of LHFRS was assessed with the construc-
tion of univariate and multivariate Cox proportional hazards model
with risk adjusting variables; age, sex, baseline systolic blood pressure,
heart rate at admission, history of HF, history of diabetes mellitus, left
ventricular ejection fraction (LVEF), hemoglobin, serum creatinine,
blood urine nitrogen, sodium, brain natriuretic peptide, C-reactive pro-
tein, and prescription of beta-blocker and angiotensin converting en-
zyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) at
admission. All variables were selected a priori as they were either pre-
dictors of risk in HF or because of their ability to confound the results.
Graphical inspection of Schoenfield residuals plotted against time was
performed to ensure that proportional hazards assumption was not vi-
olated. To examine the discriminatory ability of the LHFRS stratification,
Kaplan-Meier curves were estimated, and log-rank tests were per-
formed to assess differences in survival curves. The Hosmer-Lemeshow
test was used to estimate the model calibration. Complete case analysis
was employed for missing data. All statistical analyses were performed
with the statistical software R (Version 3.1.2, Vienna, Austria). A two-
sided p-value b 0.05 was considered statistically significant.
3. Results
3.1. Baseline characteristics
The baseline characteristics of the study population stratified by
LHFRS score are presented in Table 1. The median LHFRS value was 1
(IQR: 0–2). Patients with higher LHFRS scores were older, predomi-
nantly males and with lower admission systolic or diastolic blood pres-
sure compared to patients with lower LHFRS scores. Additionally, they
had worse renal function and higher admission RDW. In contrast, pa-
tients with LHFRS 0 or 1 exhibited higher values of sodium than those
with LHFRS 2–4. Regarding medical therapy at admission, beta-
blockers, mineralocorticoid receptor antagonists (MRAs), and loop di-
uretics were more frequently noted in higher, while ARBs were noted
in lower LHFRS categories.
3.2. Performance of the Larissa Heart Failure Risk Score
During a median follow-up of 365 (IQR: 161–365) days, the primary
and secondary outcome measures were observed in 321 and 157 pa-
tients, respectively (Supplementary Table 1). Fig. 1A and B shows the
Kaplan-Meier survival curves for the primary and the secondary out-
comes stratified by each LHFRS. The curves are separated and trends con-
sistent. The log-rank test for both outcomes produced a p-value of
b0.001, indicating statistically significant differences in survival curves
for both outcomes. Similarly, patients with higher LHFRS values (≥2)
had significantly worse prognosis compared to those with lower LHFRS
(b2) in both the primary and the secondary outcomes (p b 0.001 and
p = 0.0012, respectively, Fig. 1C and D).
In the univariate analysis, the LHFRS was found to be a significant
predictor for both the primary (hazard ratio [HR] (per 1-point increase):
1.27, 95% CI: 1.15–1.40, p b 0.001) and the secondary outcomes (HR:
1.35, 95% CI: 1.17–1.54, p b 0.001). Even after multivariable adjustment,
LHFRS remained an independent predictor of both the primary (ad-
justed HR [per 1-point increase]: 1.17, 95% CI: 1.04–1.32, p = 0.011)
and the secondary outcomes (adjusted HR: 1.31, 95% CI: 1.12–1.55,
p = 0.001). The predictive ability of LHFRS was similar in patients
with de-novo HF and those with acutely decompensated chronic HF
for both the primary (p for interaction = 0.383) and secondary out-
comes (p for interaction = 0.557). In addition, significant interactions
between the predictive value of LHFRS and LVEF or sex were not ob-
served (p for interaction N0.1 for both).
We also examined the predictive value of LHFRS as a categorical var-
iable using the median value as a cut-off (LHFRS: 0–1 vs LHFRS: 2–4).
Patients with higher LHFRS (≥2) had a significantly higher risk for all-
cause death and/or HF rehospitalization than those with lower LHFRS
(b2) as demonstrated by the univariate (HR: 1.58, 95% CI: 1.27–1.96,
p b 0.001) and multivariable analyses (adjusted HR: 1.40, 95% CI:
1.07–1.83, p b 0.014). Similarly, the risk of all-cause mortality in patients
with higher LHFRS was significantly higher than those with lower
 T. Kitai et al. / International Journal of Cardiology 307 (2020) 119–124 121

Table 1
Baseline characteristics of the study population.

LHFRS 0 1 2 3 4 p-Value
(N = 291) (N = 283) (N = 246) (N = 122) (N = 22)

Age, years 76.8 ± 13.5 77.2 ± 12.3 73.8 ± 13.8 73.3 ± 13.0 78.2 ± 11.3 0.003
Male 155 (53.3) 176 (62.2) 156 (63.4) 61 (50.0) 17 (77.3) 0.007
Ambulance 168 (57.7) 158 (55.8) 136 (55.3) 61 (50.0) 10 (45.5) 0.562
Systolic BP, mmHg 159 ± 35 155 ± 36 140 ± 32 127 ± 32 125 ± 40 b0.001
Diastolic BP, mmHg 90 ± 25 87 ± 26 84 ± 23 76 ± 21 77 ± 28 b0.001
Heart rate, beats/min 101 ± 29 99 ± 28 105 ± 32 93 ± 25 88 ± 23 0.001
De novo heat failure 192 (66.0) 115 (40.6) 126 (51.2) 45 (36.9) 6 (27.3) b0.001
LVEF
b35% 99 (35.2) 97 (35.7) 114 (48.9) 66 (55.0) 10 (45.5)
35–50% 84 (29.9) 90 (33.1) 61 (26.2) 26 (21.7) 8 (36.4) 0.001
N50% 98 (34.9) 85 (31.2) 58 (24.9) 28 (23.3) 4 (18.2)
Hypertension 291 (100.0) 283 (100.0) 78 (31.7) 0 (0.0) 0 (0.0) b0.001
Diabetes mellitus 92 (31.6) 131 (46.3) 83 (33.7) 39 (32.0) 7 (31.8) 0.002
COPD 26 (8.9) 28 (9.9) 21 (8.5) 10 (8.2) 1 (4.5) 0.914
Coronary artery disease 0 (0.0) 156 (55.1) 78 (31.7) 32 (26.2) 22 (100.0) b0.001
Βeta-blockers 100 (34.6) 117 (41.6) 104 (42.4) 63 (51.6) 12 (57.1) 0.011
ACEI 44 (15.1) 54 (19.1) 38 (15.4) 26 (21.3) 5 (22.7) 0.405
ARB 115(39.5) 97 (34.3) 54 (22.0) 20 (16.4) 3 (13.6) b0.001
MRA 35 (12.0) 60 (21.2) 56 (22.8) 53 (43.4) 9 (40.9) b0.001
Loop diuretics 107 (37.2) 154 (55.2) 109 (44.5) 81 (66.4) 17 (77.3) b0.001
BNP, pg/mL 730 [420, 1167] 751 [470, 1404] 753 [451, 1388] 872 [525, 1636] 928 [439, 1999] 0.09
Hemoglobin, g/dL 12.87 ± 1.85 12.36 ± 1.68 12.87 ± 1.97 12.25 ± 1.78 11.40 ± 1.06 b0.001
BUN, mg/dL 21 [16, 28] 25 [18, 34] 22 [17, 30] 26 [19, 40] 27 [18, 35] b0.001
Creatinine, mg/dL 1.0 [0.8, 1.4] 1.2 [0.9, 1.7] 1.0 [0.8, 1.4] 1.1 [0.8, 1.6] 1.1 [1.0, 1.3] b0.001
Na+, mEq/L 139.57 ± 4.17 139.22 ± 4.85 138.32 ± 4.35 138.38 ± 4.19 136.41 ± 5.07 b0.001
C-reactive protein, mg/L 0.5 [0.2, 2.3] 0.6 [0.2, 1.8] 0.7 [0.2, 1.7] 0.9 [0.4, 2.1] 1.5 [0.4, 3.4] 0.063
RDW, % 13.76 ± 0.69 14.99 ± 1.72 14.65 ± 1.78 16.01 ± 2.22 17.19 ± 2.74 b0.001

LHFRS = Larissa Heart Failure Risk Score; BP = blood pressure; LVEF = left ventricular ejection fraction; COPD = chronic obstructive pulmonary disease; ACEI = angiotensin converting
enzyme inhibitor; ARB = angiotensin receptor blocker; MRA = mineralocorticoid receptor antagonist; BNP = brain natriuretic peptide; BUN = blood urea nitrogen; and RDW = red
blood cell distribution width.

LHFRS in the univariable (HR: 1.67, 95% CI: 1.22–2.28, p = 0.001) and
the multivariable analyses (HR: 1.60, 95% CI: 1.09–2.34, p = 0.015).
The Hosmer-Lemeshow test revealed an excellent goodness of fit
(observed versus predicted outcomes) regarding LHFRS for the primary
and the secondary outcomes (p N 0.99 and p = 0.99, respectively).
Additionally, the LHFRS showed a stepwise increase of excess risk of
both primary and secondary outcomes, alongside linear increasing
risks or predicted risks (Fig. 2).
Of note, the performance of the LHFRS was not impaired even when
we did not exclude patients with hemoglobin levels b10 g/dL,

Fig. 1. Kaplan-Meier curves for the primary and secondary outcomes stratified by the each LHFRS (A and B), and high versus low values based on its median value (≥2 vs b2, C and D).
122 T. Kitai et al. / International Journal of Cardiology 307 (2020) 119–124
Fig. 2. Comparisons between observed versus predicted risks of primary (A) and
secondary outcome measures (B) stratified by the Larissa Heart Failure Risk Score
(LHFRS).
malignancy, or sepsis (n = 1363, Supplementary Fig. S1). The higher
LHFRS was significantly associated with an increased risk of both the
primary outcome (adjusted HR [per 1-point increase]: 1.15, 95% CI:
1.05–1.26, p = 0.003) and the secondary outcome (adjusted HR: 1.19,
95% CI: 1.06–1.36, p = 0.004). The results of Hosmer-Lemeshow tests
were p = 0.91 for the primary outcome measure and p = 0.45 for the
secondary outcome measure (Supplementary Fig. S2).
4. Discussion
The current analysis was an external validation of LHFRS in a cohort
of patients hospitalized with AHF from the REALITY-AHF registry.
Higher LHFRS values were found to strongly correlate with patients
experiencing an event demonstrating an association of LHFRS with all-
cause mortality and HF readmission.
The role of risk scores in AHF is of great importance as they can be
used as prognostic tools and can guide the clinical decision making, es-
pecially in situations where the latter must be timely and accurate. Most
importantly, close patient monitoring after HF exacerbation requiring
hospitalization or emergency department visit is associated with better
outcomes [11,12]. However, the majority of risk scores consists of sev-
eral variables [4] and requires the use of calculators, making their use
problematic in daily clinical practice. For example, the OPTIMIZE-HF
score includes 12 variables [13], whereas the ESCAPE, ELAN-HF and
APACHE-HF risk models include eight variables each [14–16]. Our
score consists of only three variables or in other words two questions
from the patient's pre-admission medical history and one parameter
from the complete blood count (CBC) at admission. The LHFRS is easily
obtainable, and of negligible low cost. Furthermore, a consistent rela-
tionship between the LHFRS and the risk of the outcome was observed
in the current analysis and score values ≥2 were associated with 40%
higher risk versus that associated with values b2, for 1-year adverse out-
comes. Given its simplicity and the fact that not all of risk scores pro-
posed for HF patients so far have been externally validated in an
independent cohort, LHFRS is one of the reliable risk scores clinically ap-
plicable. Thus, the use of LHFRS may facilitate the clinical decision mak-
ing, and triage care plans, and necessary follow-up. Moreover, an
important characteristic of LHFRS is its ability to discriminate the
long-term risk (i.e. 1 year) of patients initially admitted with AHF. AHF
risk models are often constructed to predict the short-term outcomes
[4,17] based on the fact that outcomes during hospitalization or up to
6 months from admission may seem more relevant to acute pathologies,
such as AHF syndromes. However, long-term outcomes (i.e. 1 year from
admission) are clinically relevant, despite the limited number of long-
term prognostic models developed in AHF [18–20]. For example, the ad-
ministration of inotropes in the acute setting may have favorable short-
term but neutral or even deleterious long-term effects [21,22]. Taken to-
gether, LHFRS demonstrated a good discriminatory ability in our study
although it is the most parsimonious long-term risk score in AHF
(Fig. 3). Admittedly, however, the BIOSTAT and SEATTLE HF models
are more sophisticated [23,24].
The LHFRS consists of three variables: hypertension history, coro-
nary artery disease/myocardial infarction history, and RDW that have
been well established risk factors for various cardiovascular diseases.
Hypertension or high blood pressure is a well-known risk factor for sev-
eral health conditions, including HF. However, low blood pressure is an
adverse risk factor whereas hypertension may serve as a protective
mechanism in some hospitalized patients with HF, contrary to what is
expected in the normal population [5]. The concept of “reactive hyper-
tension”, which suggests the presence of a functional cardiac reserve
during acute physiological stress, may be a reasonable explanation. Pa-
tients with lower functional cardiac reserve and lower blood pressure
even in acute situations (i.e. admission for HF), exhibit worse prognosis
compared to those with higher values of blood pressure [25]. Another
possible explanation is that patients with low blood pressure cannot tol-
erate life-saving medical therapies, such as beta-blockers, ACEI/ARB, or
MRAs due to their blood pressure lowering effect. Gheorghiade et al.
found that low blood pressure (b120 mmHg) on admission was an inde-
pendent adverse risk factor of prognosis in the population of the
OPTIMIZE-HF registry [26]. Prior history of myocardial infarction or cor-
onary artery disease is also a risk factor of adverse prognosis [27]. The
strong interplay between HF and myocardial infarction has been dem-
onstrated in several studies [28]. RDW is a common and inexpensive
laboratory parameter of the CBC test that expresses the variability of
the size of RBCs and has been traditionally used for the classification
of different types of anemia [29]. There has been increasing evidence
confirming that increased RDW is associated with poor prognosis in pa-
tients with cardiovascular disease [6,30–33]. Interestingly, it has been
reported that RDW doesn't change significantly during hospitalization
for HF [34].
4.1. Strengths and limitations
Calibration and discrimination are important aspects of a prediction
model and consider the full range of predicted risks. However, these as-
pects do not assess clinical usefulness, i.e. the ability to make better de-
cisions with a model than without [35]. A clinical prediction model
should be used to guide decisions. In this regard, a cut-off is required
to classify patients as either low risk (no or standard treatment) or
high risk (standard treatment or intensified treatment). The major lim-
itation of the LHFRS is that it currently cannot be used to guide treat-
ment in AHF. However, AHF treatment is problematic in view of the
multitude inconclusive studies [36] and this is to a great extent related
 T. Kitai et al. / International Journal of Cardiology 307 (2020) 119–124 123

Fig. 3. Most prognostic risk models were multivariable. The LHFRS is the most parsimonious risk score in HF and consists of only three variables (hypertension history, coronary artery
disease/myocardial infarction history, and red blood cell distribution width). Its calculation is very easy and does not require the use of sophisticated calculators. The increase in the
LHFRS is associated with the incremental increase of adverse events risk. LHFRS = Larissa Heart Failure Risk Score; HTN = hypertension; CAD = coronary artery disease; MI =
myocardial infarction; RDW = red blood cell distribution width.

to the ongoing debate regarding the underlying pathophysiology [37].
Despite these limitations, patients with a high LHFRS score may benefit
from organ damage protection, standardized management programs,
including immediate identification and management of cardiogenic
shock, and establishment of HF networks for close monitoring of this
high-risk subgroup [38]. A 1-year prognosis may be affected by numer-
ous factors post-discharge. However, in the present study all variables
entered in the Cox models were collected at admission. Therefore, po-
tential confounders during hospital course and post-discharge cannot
be excluded.
5. Conclusion
The current analysis showed an external validation of LHFRS in a co-
hort of patients hospitalized with AHF from the REALITY-AHF registry.
Higher LHFRS values were found to be associated with an increased
risk of all-cause mortality and/or HF readmission. LHFRS is very easily
calculated and can be used as a risk stratification tool in patients hospi-
talized for AHF.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijcard.2019.12.051.
Funding/acknowledgement
None.
Declaration of competing interest
None.
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