ESC HEART FAILURE
ORIGINAL ARTICLE
ESC Heart Failure 2024; 11: 702–708
Published online 20 December 2023 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.14631

Geriatric Nutritional Risk Index predicts bleeding eventin patients with heart failure
Yu Sato1, Akiomi Yoshihisa1,2*, Yuji Nozaki1, Himika Ohara1, Yukiko Sugawara1, Satoshi Abe1,
Tomofumi Misaka1, Takamasa Sato1, Masayoshi Oikawa1, Atsushi Kobayashi1, Takayoshi Yamaki1,
Kazuhiko Nakazato1 and Yasuchika Takeishi1
1
Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan; and 2Department of Clinical Laboratory Sciences, Fukushima Medical University,
Fukushima, Japan

Abstract
Aims We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients withheart failure.
Methods and results We evaluated the nutritional status of patients with heart failure [n = 2044, median (inter-quartile
range) age 69.0 (59.0–78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint
was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classiﬁcation and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We
divided the patients into two groups based on GNRI levels: high GNRI group (GNRI ≥ 106.2, n = 606, 29.6%) and low GNRI
group (GNRI < 106.2, n = 1438, 70.4%). We compared the patients’ characteristics and prognosis between the two groups.
The low GNRI group was older [72.0 (63.0–79.0) vs. 63.0 (53.0–73.0) years, P < 0.001] and had a lower prevalence of malesex (56.9% vs. 64.5%, P = 0.001). There were no differences in the use of antiplatelet agents and anticoagulants between
the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3–667.4) vs. 111.6 (42.6–235.4) pg/mL,
P < 0.001] and levels of haemoglobin were lower [12.4 (10.8–13.7) vs. 14.2 (12.9–15.4) g/dL, P < 0.001] in the low GNRI
group. The Kaplan–Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank
P < 0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% conﬁdence
interval 1.002–3.805, P = 0.049) was associated with bleeding events.
Conclusions Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding
event rates. Comprehensive management is required to avoid bleeding event in those populations.
Keywords

Malnutrition; Bleeding; Haemorrhage; Heart failure

Received: 4 May 2023; Revised: 10 October 2023; Accepted: 23 November 2023
*Correspondence to: Akiomi Yoshihisa, Department of Cardiovascular Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. Tel: +81-24-5471190; Fax: +81-24-548-1821. Email: yoshihis@fmu.ac.jp

Introduction
Heart failure (HF) affects nutritional status, and up to halfof the patients with HF are reported to be malnourishedby broader deﬁnitions.1 Among many assessment tools ofnutritional status, the Geriatric Nutritional Risk Index(GNRI) effectively stratiﬁes patients with HF and predicts
mortality.2,3 The clinical impact of GNRI has been evaluatedin patients with multiple diseases, and patients with low
GNRI are considered to be at risk of malnutrition, more in-ﬂammation, and worse outcomes.4–8 Chronic inﬂammation
plays a key role in atherosclerosis9 and leads to bleeding
events.10,11 However, the association between GNRI andbleeding events in patients with HF has been unclear. It is
crucial to elucidate this issue, because cardiac event rate
and all-cause mortality increase after bleeding events in patients with HF.12 In the present study, we evaluated patients with HF using GNRI and compared bleeding event
rates between those with high GNRI and those with low
GNRI.

© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modiﬁcations or adaptations are made.

Methods
Study population
This was an observational study. Patient ﬂowchart is shown in
Figure 1. We recruited data on a total of 2437 patients who
were hospitalized for decompensated HF at Fukushima Medical University Hospital and discharged between January 2009and December 2019. Nutritional status was evaluated using
GNRI. GNRI was calculated in a stable condition within 1 weekprior to discharge using the following formula reported by
Bouillanne et al.: GNRI = [14.89 × albumin (g/dL)] + [41.7 × (body weight / ideal body weight by Lorentz
equation)].2 Patients who lacked data on GNRI (n = 254)
and those who were on maintenance dialysis (n = 139) were
excluded. Finally, a total of 2044 remaining patients (medianage 69.0 years, 59.1% males) were analysed. Laboratory andechocardiographic data obtained within 1 week prior to discharge were used for analyses. Data on medication werebased on prescriptions at discharge. Regarding antiplatelet
agents, we also speciﬁed whether they were used as single
or dual antiplatelet therapy. It was also compared whether
oral anticoagulants were used alone or in combination with
antiplatelet agents. Considering the protocols of previous
major clinical trials,13,14 we set the primary endpoint of thisstudy as bleeding events deﬁned as haemorrhagic stroke
and/or gastrointestinal bleeding. The deﬁnitions of
haemorrhagic stroke and gastrointestinal bleeding were in accordance with those in our previous study.15 Because this was
the ﬁrst to evaluate the impact of nutritional status as a
bleeding risk in patients with HF, we sought the appropriate
cut-off point of GNRI in predicting the primary endpoint using

the survival classiﬁcation and regression tree analysis, an implementation of conditional inference trees that embedtree-structured regression models into a well-deﬁned theoryof conditional inference procedures,16 and divided patients
into two groups based on the cut-off point.
The investigation conforms to the principles outlined in the
Declaration of Helsinki.17 The study protocol was approved by
the ethical committee of Fukushima Medical University. All
patients gave written informed consent to participate in thisstudy.

Statistical analysis
All continuous variables analysed in this study were nonnormally distributed according to the Shapiro–Wilk test andpresented as median (inter-quartile range). Categorical variables
were presented as numbers (%). We compared continuousand categorical variables using the Mann–Whitney U testand χ 2 test, respectively. The accumulated incidence of the
bleeding events was compared using the Kaplan–Meier analysis with log-rank test between the two groups. We assessed
the association of GNRI and the primary endpoint using theCox proportional hazard analysis. A hazard ratio was adjusted
for two models: Model 1 (adjusted for age and sex) andModel 2 (adjusted for Model 1 and variables with P valuesof <0.1 in the univariable analysis). If one patient experienced
two or more primary endpoints, the ﬁrst event was enteredinto the analyses. P values of <0.05 were considered statistically signiﬁcant in all analyses. The survival classiﬁcation andregression tree analysis was conducted using EZR Version 1.40
(Saitama Medical Center, Jichi Medical University, Saitama,

Figure 1 Patient ﬂowchart. GNRI, Geriatric Nutritional Risk Index.

ESC Heart Failure 2024; 11: 702–708
DOI: 10.1002/ehf2.14631

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GNRI predicts bleeding event in HF patients

Y. Sato et al.

Japan), which is a graphical user interface for R (The R
Foundation for Statistical Computing, Vienna, Austria).18 Allother analyses were performed using IBM SPSS Statistics
Version 28.0.1.0 (IBM, Armonk, NY, USA).

Results
According to the survival classiﬁcation and regression tree
analysis (Figure 1), the accurate cut-off point in predicting
the primary endpoint was 106.2, according to which the patients were divided into the high GNRI group (patients withGNRI ≥ 106.2, n = 606, 29.6%) and low GNRI group (thosewith GNRI < 106.2, n = 1438, 70.4%).
The comparisons of patient characteristics are summarizedin Table 1. The low GNRI group was older (72.0 vs. 63.0 years,
P < 0.001) and had a lower prevalence of male sex (56.9% vs.
64.5%, P = 0.001). In terms of bleeding risks, the low GNRI
group had lower systolic blood pressure (121.0 vs.
123.0 mmHg, P = 0.035) and higher prevalence of atrial ﬁbril-lation (42.1% vs. 34.3%, P < 0.001). However, the use of antiplatelet agents and anticoagulants was comparable between the two groups. The use of proton pump inhibitor
was more prevalent in the low GNRI group (65.2% vs.
60.4%, P = 0.038). In the laboratory data, the low GNRI group
had higher levels of B-type natriuretic peptide (321.1 vs.
111.6 pg/mL, P < 0.001) and lower levels of haemoglobin(12.4 vs. 14.2 g/dL, P < 0.001) and estimated glomerular ﬁltration rate (56.2 vs. 61.7 mL/min/1.73 m2). In the echocardiographic data, left ventricular ejection fraction was comparable between the two groups.
During the post-discharge follow-up period, median
1378 days, there were 115 bleeding events (34 cases of
haemorrhagic stroke, 80 cases of gastrointestinal bleeding,and 1 case of both haemorrhagic stroke and gastrointestinal
bleeding). The Kaplan–Meier analysis demonstrated that theaccumulated bleeding event rate was higher in the low GNRI
group (Figure 2, log-rank P < 0.001). Moreover, the accumulated each event rates of haemorrhagic stroke and gastrointestinal bleeding were also higher in the low GNRI group(Figure 3, log-rank P = 0.009 and 0.004, respectively). The

Table 1 Patient characteristics (n = 2044)

GNRI
Albumin (g/dL)
Body weight (kg)Age (years)
Male sex, n (%)
Systolic BP (mmHg)
Hypertension, n (%)
Diabetes mellitus, n (%)
CAD, n (%)
Atrial ﬁbrillation, n (%)
RASIs, n (%)
Beta-blockers, n (%)
Loop diuretics, n (%)
Antiplatelet agents, n (%)
Status of antiplatelet agents, n (%)
None
SAPT
DAPT
OACs, n (%)
Status of OACs, n (%)
NoneMonotherapy
Combination
PPIs, n (%)
BNP (pg/mL)
Haemoglobin (g/dL)
2
eGFR (mL/min/1.73 m )LVEF (%)
Type of HF, n (%)
HFrEF
HFmrEF
HFpEF

Total (n = 2044)

High GNRI group (n = 606)

Low GNRI group (n = 1438)

P value

99.8 (91.5–108.2)
3.8 (3.4–4.2)
57.5 (49.3–66.9)
69.0 (59.0–78.0)1209 (59.1)
122.0 (108.0–139.0)
1360 (66.5)
774 (37.9)
599 (29.3)
814 (39.8)
1405 (68.7)
1463 (71.6)
1393 (68.2)
987 (48.3)

112.8 (109.2–117.2)
4.3 (4.1–4.5)
68.1 (59.6–78.5)
63.0 (53.0–73.0)
391 (64.5)
124.0 (110.0–138.0)
419 (69.1)
230 (38.0)
172 (28.4)
208 (34.3)
441 (72.8)
442 (72.9)366 (60.4)
286 (47.2)

95.3 (88.3–100.5)
3.7 (3.2–4.0)
53.7 (46.6–61.4)
72.0 (63.0–79.0)
818 (56.9)
121.0 (106.0–139.0)
941 (65.4)
544 (37.8)427 (29.7)
606 (42.1)
964 (67.0)
1021 (71.0)1027 (71.4)
701 (48.7)<0.001<0.001<0.001<0.001
0.001
0.035
0.105
0.958
0.552
<0.0010.011
0.376<0.0010.521
0.188

1057 (51.7)
614 (30.0)
373 (18.2)
1190 (58.2)
854 (41.8)
617 (30.2)
573 (28.0)1304 (63.8)
225.3 (81.1–549.9)
12.9 (11.3–14.4)
58.1 (44.3–71.7)
54.6 (39.5–64.0)
390 (25.6)
237 (15.6)
897 (58.9)

320 (52.8)
166 (27.4)
120 (19.8)
349 (57.6)
257 (42.4)
191 (31.5)
158 (26.1)
366 (60.4)
111.6 (42.6–235.4)
14.2 (12.9–15.4)
61.7 (48.8–74.8)
56.3 (41.8–65.0)
106 (23.0)
66 (14.3)
288 (62.6)

737 (51.3)
448 (31.2)
253 (17.6)
841 (58.5)
597 (41.5)
426 (29.6)
415 (28.9)
938 (65.2)
321.1 (123.3–667.4)
12.4 (10.8–13.7)
56.2 (41.8–70.5)
54.0 (39.0–63.5)

0.708
0.413

0.038
<0.001<0.001<0.0010.058
0.145

284 (26.7)
171 (16.1)
609 (57.2)

BNP, B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular ﬁltration rate; GNRI, Geriatric Nutritional Risk Index; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction;
HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; OACs, oral anticoagulants; PPIs, proton pump inhibitors; RASIs, renin–angiotensin system inhibitors; SAPT, single antiplatelet
therapy.

ESC Heart Failure 2024; 11: 702–708
DOI: 10.1002/ehf2.14631

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705

Figure 2 Kaplan–Meier analysis: composite endpoint. The occurrence of the composite of haemorrhagic stroke or gastrointestinal bleeding was higher
in the low Geriatric Nutritional Risk Index (GNRI) group than in the high GNRI group during the post-discharge follow-up period (P < 0.001).

Figure 3 Kaplan–Meier analysis: detailed bleeding events. When haemorrhagic stroke and gastrointestinal bleeding were analysed separately, the occurrence of both events was higher in the low Geriatric Nutritional Risk Index (GNRI) group than in the high GNRI group (P = 0.009 and 0.004,
respectively).

multivariable Cox proportional hazard analysis revealed thatlow GNRI as a categorical variable (hazard ratio 1.952, 95%
conﬁdence interval 1.002–3.805, P = 0.049) was independently associated with bleeding events (Table 2, Model 2).

Discussion
This present study revealed that ~70% of patients with HF
were under the cut-off point of GNRI regarding bleeding

event. Contrary to the lower blood pressure, similar use of
antithrombotic agents, and higher use of proton pump inhibitors in the low GNRI group, low GNRI was independently associated with the composite endpoint of haemorrhagic stroke
and/or gastrointestinal bleeding. These ﬁndings are important because they suggest that clinicians should provide advanced comprehensive care beyond blood pressure control
and antithrombotic management to avoid bleeding eventsin malnourished patients with HF.
The association between malnutrition and inﬂammation
has been observed in patients who are at high bleeding risk,
ESC Heart Failure 2024; 11: 702–708
DOI: 10.1002/ehf2.14631

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GNRI predicts bleeding event in HF patients

Y. Sato et al.

Table 2 Cox proportional hazard analysis for bleeding events (event n = 115/2044 patients)

Low GNRI (vs. high GNRI)
Low GNRI (vs. high GNRI) Model 1
Low GNRI (vs. high GNRI) Model 2
GNRI (continuous variable)
GNRI (continuous variable) Model 1
GNRI (continuous variable) Model 2

Hazard ratio

95% conﬁdence interval

P value

2.567
2.297
1.952
0.968
0.970
0.991

1.552–4.245
1.374–3.842
1.002–3.805
0.956–0.981
0.957–0.983
0.969–1.013<0.001
0.002
0.049<0.001<0.001
0.432

GNRI, Geriatric Nutritional Risk Index.
Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, systolic blood pressure, atrial ﬁbrillation, renin–angiotensin system inhibitors, loop diuretics, proton pump inhibitors, log-transformed B-type natriuretic peptide, haemoglobin, estimated glomerular ﬁltration
rate, and left ventricular ejection fraction.

such as those with end-stage renal disease and coronary artery disease.10,19 In those populations, malnutrition and inﬂammation make a vicious cycle called malnutrition–
inﬂammation–atherosclerosis syndrome, which results inlow quality of life and high mortality.10,20 In addition to thishypothesis, this study indicated other mechanisms between
malnutrition and bleeding events. Considering the patients’characteristics, levels of B-type natriuretic peptide werehigher in the low GNRI group, suggesting that congestion
was more severe in that group.21,22 Right heart congestion
causes intestinal congestion and alters gastrointestinal function, which results in gastrointestinal bleeding.12,23–25 In addition, hypoperfusion is another aspect of severe HF.26 Lower
blood pressure in the low GNRI group indicated low cardiac
output and advanced HF.27 Abdominal hypoperfusion also
causes abdominal symptoms, intestinal dysfunction, and gastrointestinal bleeding.12,25,28,29 In addition to abdominal congestion that causes early satiety and nausea, chronic inﬂammation and consequent metabolic disturbance induce
malnutrition and cachexia, making a vicious cycle.30 Other
characteristics of the low GNRI group that were associatedwith bleeding events included age,31–33 female sex,34,35 lower
levels of haemoglobin,32,36 and lower levels of estimated glomerular ﬁltration rate.32,37
The cut-off value, GNRI of 106.2, for predicting bleeding
events in patients with HF was close to the boundary between no and low nutritional risks.2 This result suggests thatbleeding risk easily increases with a small deterioration of nutritional status in patients with HF. To assess the nutritional
status, body mass index is one of the simplest assessment
tools.38 However, body mass index is inappropriate to predict
bleeding events because both low and high body mass indexes are associated with major bleeding.32 Some patientswith high body mass index have sarcopenic obesity, whichis associated with high mortality.39 The major conditions ofmalnutrition are traditionally classiﬁed as marasmus,

kwashiorkor, or both.40 Marasmus is inadequate
energy-calorie intake and presents with low body weight,
whereas kwashiorkor is a protein deﬁciency resulting in
hypoalbuminaemia.40 Thus, GNRI, which uses albumin andbody weight comprehensively, is an appropriate tool forevaluating nutritional status.
The present study had some limitations. First, we did notcollect data on highly sensitive C-reactive protein as a marker
of inﬂammation. Second, doses of antiplatelet agents and anticoagulants were not analysed.
In conclusion, we evaluated nutritional status of patientswith HF and found a threshold of GNRI for bleeding event.
The threshold of GNRI was relatively low, and patients withlow GNRI showed more severe HF status. Low GNRI was independently associated with bleeding events. Patients withpoor nutritional status require comprehensive management
including prevention of bleeding events.

Acknowledgements
The authors thank Ms Kumiko Watanabe, Ms Yumi Yoshihisa,
and Ms Tomiko Miura for their technical assistance.

Conﬂict of interest
None declared.

Funding
This work was supported by Grants-in-Aid for Scientiﬁc Research (Grant Numbers 20K07828 and 22K15670) from theJapan Society for the Promotion of Science.

ESC Heart Failure 2024; 11: 702–708
DOI: 10.1002/ehf2.14631

20555822, 2024, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14631 by Cochrane Japan, Wiley Online Library on [29/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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