Appetite loss at discharge from acute decompensated heart failure: Observation from KCHF registry.

OBJECTIVE: The complex link between nutritional status, protein and lipid synthesis, and immunity plays an important prognostic role in patients with heart failure. However, the association between appetite loss at discharge and long-term outcome remains unclear.
METHODS: The Kyoto Congestive Heart Failure registry is a prospective cohort study that enrolled consecutive patients hospitalized for acute decompensated heart failure (ADHF) in Japan. We assessed 3528 patients alive at discharge, and for whom appetite and follow-up data were available. We compared one-year clinical outcomes in patients with and without appetite loss at discharge.
RESULTS: In the multivariable logistic regression analysis using 19 clinical and laboratory factors with P value < 0.1 by univariate analysis, BMI < 22 kg/m2 (odds ratio (OR): 1.57, 95% confidence interval (CI): 1.11-2.24, P = 0.01), CRP >1.0mg/dL (OR: 1.49, 95%CI: 1.04-2.14, P = 0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99-6.22, P<0.001) were associated with an increased risk of appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39-0.83, P = 0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50-0.98, P = 0.04) were related to a decreased risk in the presence of appetite loss. The cumulative 1-year incidence of all-cause death (primary outcome measure) was significantly higher in patients with appetite loss than in those without appetite loss (31.0% vs. 15.0%, P<0.001). The excess adjusted risk of appetite loss relative to no appetite loss remained significant for all-cause death (hazard ratio (HR): 1.63, 95%CI: 1.29-2.07, P<0.001).
CONCLUSIONS: Loss of appetite at discharge was associated with worse 1-year mortality in patients with ADHF. Appetite is a simple, reliable, and useful subjective marker for risk stratification of patients with ADHF.

Introduction

The complex link between nutritional status, protein and lipid synthesis, and immunity plays an important prognostic role in patients with heart failure (HF), although its role in acute decompensated HF (ADHF) remains to be elucidated. Several studies have reported an association between nutritional status and prognosis of heart failure patients [1-3]. Recently, several scoring systems have been reported to be associated with the prognosis of heart failure patients. The Prognostic Nutritional Index (PNI), which was originally developed for the prediction of postoperative complications, mainly in surgical patients, was associated with mortality in patients with heart failure [4]. Geriatric Nutritional Risk Index was also reported to be associated with prognosis in elderly heart failure patients [5]. Appetite is an important factor in improving the nutritional status of patients with heart failure.

Appetite is a desire for food and can be influenced by physical conditions such as blood sugar levels, hormones, and exercise. It can also be driven by mood and emotions and is assessed by healthcare providers in history-taking. In patients with ADHF, several residual symptoms at discharge such as pulmonary congestion, pitting edema, and pleural effusion were reportedly associated with long-term outcomes [6-9]. Although in the past years there were at least few important papers published concerning the issue of appetite loss and anorexia/cachexia syndrome in heart failure[3,10-13], there is still scarcity in the studies focused on “appetite loss,” a subjective symptom in patients with heart failure [10,13]. This study aimed to clarify the characteristics of patients with appetite loss at discharge from ADHF and investigate the association between appetite loss at discharge and clinical outcomes at 1-year in patients with ADHF in Japan.

Methods

Study population

The Kyoto Congestive Heart Failure (KCHF) registry is a physician-initiated, prospective, observational, multicenter cohort study enrolling consecutive patients who were admitted because of ADHF for the first time between October 2014 and March 2016 in 19 secondary and tertiary hospitals, including rural and urban, and large and small hospitals in Japan. The details of the KCHF registry have been described previously [14]. The KCHF registry enrolled all patients with acute decompensated heart failure defined by the modified Framingham criteria who were admitted to the participating centers and underwent heart failure-specific treatment involving intravenous drugs within 24 hours after hospital presentation. The study protocol was approved by the institutional review board of each participating center. Patient records were anonymized prior to the analysis. Written informed consent was waived by the institutional review boards of Kyoto University and each participating center, as the study met the conditions outlined in the Japanese ethical guidelines for medical and health research involving human subjects [15]. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Ethics

The study conformed to the principles outlined in the Declaration of Helsinki. The study protocol was approved by the ethics committees of each participating hospital. The approval number is provided in the supplementary appendix. Patient records were anonymized prior to the analysis. As the study met the conditions of the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects [16], the institutional review boards of Kyoto University and each participating center waived the need to obtain written informed consent from each patient. We disclosed the details of the present study to the public as an opt-out method and clearly informed patients of their right to refuse enrollment. The details have been previously described.10

Definitions of appetite loss and other variables

In KCHF study, symptoms and physical findings were evaluated using a four-level symptomatic grading (0, None; 1, Seldom/Mild; 2, Frequent/Moderate; 3, Continuous/Severe) at discharge [17]. As for appetite loss, attending physician asked the patient about the appetite (“Do you have an appetite?” with the response option “Yes/No”. If patients answer was “No,” the next question was “How bad is your appetite loss?” with the response option “1, Mild; 2, Moderate; 3, Severe.” “Appetite loss” was defined the presence of any grade of appetite loss. “Mild appetite loss” was defined as the presence of appetite loss of grade 1, and “moderate/severe appetite loss” was defined as the presence of grade 2 or 3. Residual edema was defined as follows; 0, no edema; 1, slight pitting edema that disappeared rapidly; 2, moderate pitting edema that may last more than 1 min; and 3, severe pitting edema that lasted more than several minutes. Patient’s ADL level was assessed on four level: (1) ambulatory (patients who can walk by themselves), (2) use wheelchair (outdoor only), (3) use wheelchair (outdoor and indoor), (4) bedridden. Other definitions for the baseline factors are provided in S1 File.

Outcomes

Clinical follow-up data were collected in October 2017. The attending physicians or research assistants at each participating hospital collected clinical events after the index hospitalization from the hospital charts or by contacting patients, their relatives, or their referring physicians with consent. Detailed definitions of clinical outcome measures have been described previously [18]. The primary outcome measure in the current analysis was all-cause death. The secondary outcome measures were cardiovascular (CV) death, non-CV death, and HF hospitalization. The causes of death were classified according to the Valve Academic Research Consortium definitions [19] and adjudicated by a clinical event committee (supplementary methods).

Patient and public involvement

This study was conducted without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient-relevant outcomes or interpret the results. The patients were not invited to contribute to the writing or editing of this document for readability or accuracy.

Statistical analysis

Categorical variables are presented as counts with percentages and compared using the χ2 test. Continuous variables were expressed as the mean with standard deviation or median with interquartile range (IQR) and compared using the Student’s t-test or the Wilcoxon rank-sum test, as appropriate. To determine the factors associated with appetite loss at discharge, we compared the clinical characteristics and the presence or absence of appetite loss at discharge. A multivariable logistic regression model was developed to identify clinical characteristics, laboratory data, and medications at discharge that were independently associated with the presence of appetite loss using 19 factors with P value < 0.1 by univariate analysis extracted from the variables listed in Table 1. The results are expressed as the odds ratios (ORs) with their 95% confidence intervals (CIs). The Kaplan–Meier method was used to estimate the cumulative 1-year incidence of clinical events, and differences were assessed using the log-rank test. The date of discharge from the index hospitalization was regarded as time zero for the clinical follow-up. We used a multivariable Cox proportional hazard model to estimate the hazard ratios (HRs) and their 95% CIs of patients with appetite loss relative to those without appetite loss for the primary and secondary outcome measures. Proportional hazard assumptions were assessed on the plots of log (time) versus log [− log (survival)] stratified by the variables and were verified to be acceptable. Consistent with the previous reports [20-24], we selected the 30 clinically relevant risk-adjusting variables listed in Table 1. For the risk-adjusting variables, continuous variables were dichotomized by clinically meaningful reference values or median values: age ≥80 years based on the median value; left ventricular ejection fraction (LVEF) <40% based on the HF guideline of LVEF classification [25]; body mass index (BMI) <22 kg/m2; estimated glomerular filtration rate <30 mL/min/1.73m2; decreased albumin levels (serum level <3.0 g/dL); and hyponatremia (serum sodium level <135 mEq/L). As an exploratory analysis, we compared the 1-year clinical outcomes of patients with moderate/severe appetite loss, mild appetite loss, and no appetite loss. We also performed subgroup analyses stratified by age, renal function, activity of daily living (ADL), C-reactive protein (CRP) level, and type and number of medications. All statistical analyses were performed by a physician (E.Y.) and a statistician (T.M.) using JMP 13.0 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at P < 0.05.

Table 1

Baseline patient characteristics.

Variables	Appetite loss	No appetite loss	P value	N of patients analyzed
	(N = 405, 11.5%)	(N = 3123, 88.5%)
Demographics
Age, years*†	83 [75–88]	80 [71–86]	<0.001	3528
Age ≥80 years	257 (63.5)	1568 (50.2)	<0.001	3528
Men*†	192 (47.4)	1761 (56.4)	<0.001	3528
BMI, kg/m2	21.9 ± 4.2	23.0 ± 4.5	<0.001	3361
BMI <22 kg/m2*†	214 (57.2)	1337 (44.8)	<0.001	3361
Etiology			<0.001	3528
Coronary artery disease	118 (29.1)	1018 (32.6)
Acute coronary syndrome†	26 (6.4)	163 (5.2)
Cardiomyopathy	60 (14.8)	477 (15.3)
Valvular heart disease	95 (23.5)	594 (19.0)
Hypertensive heart disease	82 (20.3)	804 (25.7)
Other heart disease	50 (12.4)	230 (7.4)
Medical history
Prior hospitalization due to HF*†	177 (45.4)	1074 (34.9)	<0.001	3471
Atrial fibrillation or flutter†	178 (44.0)	1317 (42.2)	0.5	3528
Hypertension*†	267 (65.9)	2290 (73.3)	0.002	3528
Diabetes mellitus*†	129 (31.9)	1183 (37.9)	0.018	3528
Dyslipidemia	147 (36.3)	1223 (39.2)	0.27	3528
Prior myocardial infarction†	88 (21.7)	708 (22.7)	0.67	3528
Prior stroke†	68 (16.8)	488 (15.6)	0.55	3528
Current smoking*†	29 (7.4)	401 (13.0)	0.001	3480
Chronic kidney disease	202 (50.0)	1348 (43.2)	0.01	3528
Chronic lung disease†	44 (10.9)	425 (13.6)	0.13	3528
Malignancy	69 (17.0)	444 (14.2)	0.13	3528
Dementia*	107 (26.4)	504 (16.1)	<0.001	3528
Social backgrounds and activities
Living alone†	77 (19.0)	676 (21.7)	0.22	3528
Ambulatory*†	260 (65.0)	2533 (81.9)	<0.001	3493
Vital signs at presentation
Systolic blood pressure, mmHg	144 ± 35	148 ± 35	0.004	3521
Systolic blood pressure <90 mmHg†	16 (4.0)	71 (2.3)	0.04	3521
Heart rate, bpm	94 ± 27	96 ± 28	0.15	3507
Heart rate <60 bpm†	27 (6.7)	215 (6.9)	1.00	3507
Body temperature >37.5 degree Celsius	34 (9.1)	172 (5.8)	0.01	3365
NYHA Class III or IV	356 (87.9)	2708 (87.1)	0.65	3514
Tests at admission
LVEF	47 ± 17	46 ± 16	0.8	3517
HFrEF (LVEF <40%)†	142 (35.2)	1152 (37.0)
HFmrEF (LVEF 40–49%)	73 (18.1)	593 (19.1)
HFpEF (LVEF ≥50%)	189 (46.8)	1368 (43.9)
BNP, pg/mL	828 [431–1545]	700 [389–1216]	<0.001	3112
NT-proBNP, pg/mL	9080[3842–17211]	5312[2535–11457]	0.03	641
Creatinine, mg/dL	1.21 [0.85–1.81]	1.09 [0.82–1.57]	0.08	3522
eGFR, mL/min/1.73m2	38.1 [24.1–57.5]	45.3 [30.1–61.2]	<0.001	3522
eGFR <30 mL/min/1.73m2†	138 (34.2)	776 (24.9)	<0.001	3522
Blood urea nitrogen, mg/dL	26 [18–38]	23 [17–33]	<0.001	3518
Serum sodium, mEq/L	139 ± 5	139 ± 4	0.12	3515
Sodium <135 mEq/L†	60 (14.9)	348 (11.2)	0.03	3515
Hemoglobin, g/dL	11.2 ± 2.2	11.6 ± 2.4	<0.001	3523
Anemia††	292 (72.1)	2033 (65.2)	0.006	3523
Albumin, g/dL	3.4 ± 0.5	3.5 ± 0.5	<0.001	3421
Albumin <3.0 g/dL	74 (19.1)	377 (12.4)	0.003	3421
C reactive protein, mg/dL	0.73 [0.20–3.09]	0.58 [0.20–1.85]	<0.001	3206
Medication at discharge
Number of prescribed drugs	8 [6–11]	8 [6–11]	0.54	3367
ACE-Is/ARBs*†	192 (47.4)	1857 (59.5)	<0.001	3528
MRAs†	169 (41.7)	1420 (45.5)	0.15	3528
Beta-blockers*†	251 (62.0)	2112 (67.6)	0.02	3528
Diuretics†	399 (83.7)	2616 (83.8)	0.97	3528
Digitalis†	27 (6.7)	178 (5.7)	0.44	3528
Pimobendane*†	36 (8.9)	153 (4.9)	<0.001	3528
Aspirin*†	128 (31.6)	1214 (38.9)	0.005	3528
NSAIDs*†	10 (2.5)	72 (2.3)	0.84	3528
Tests at discharge
BNP, pg/mL	340 (164–646)	258 (133–499)	<0.001	2241
BNP > 200 pg/mL*	184 (70.2)	1211 (61.2)	0.005	2241
NT-proBNP, pg/mL	3917[1511–9368]	1777[736–3837]	<0.001	418
Creatinine, mg/dL	1.21 (0.86–1.86)	1.11 (0.86–1.54)	0.07	3000
eGFR, mL/min/1.73m2	38.1 (24.2–53.4)	43.9 (30.4–29.3)	<0.001	3484
eGFR <30 mL/min/1.73m2*	143 (35.9)	747 (24.2)	<0.001	3484
Blood urea nitrogen, mg/dL	29 (20–42)	25 (18–35)	<0.001	3000
Serum sodium, mEq/L	139 (136–141)	139 (137–141)	0.89	3000
Sodium <135 mEq/L	7 (1.8)	54 (1.8)	0.99	3000
Hemoglobin, g/dL	10.8 (9.8–12.1)	11.4 (9.9–13.0)	<0.001	3459
Anemia*†‡	315 (78.8)	2102 (68.7)	<0.001	3459
Albumin, g/dL	3.2 (2.9–3.5)	3.4 (3.1–3.7)	<0.001	3097
Albumin <3.0 g/dL*	102 (29.3)	511 (18.6)	<0.001	3097
C reactive protein, mg/dL	0.6 (0.2–1.4)	0.4 (0.2–1.0)	<0.001	3206
C reactive protein > 1.0mg/dL*	133 (34.8)	708 (25.1)	<0.001	3206
Residual edema*	150 (37.2)	297 (9.9)	<0.001	3511

* Risk adjusting variables selected for the multivariable logistic regression model. Nineteen factors with p-value < 0.1 by univariate analysis were selected.

† Risk adjusting variables selected for the multivariable Cox proportional hazard models.

‡ Defined by the World Health Organization criteria (hemoglobin <12 g/dL for women and <13 g/dL for men).

BMI = body mass index, HF = heart failure, PCI = percutaneous coronary interventions, CABG = coronary artery bypass graft, ACE-I = angiotensin-converting enzyme inhibitor, ARB = angiotensin II receptor blocker, MRA = mineralocorticoid receptor antagonist, HFrEF = heart failure with reduced ejection fraction, HFmrEF = heart failure with mid-range ejection fraction, HFpEF = heart failure with preserved ejection fraction, LVEF = left ventricular ejection fraction, NYHA = New York Heart Association, BNP = brain-type natriuretic peptide, eGFR = estimated glomerular filtration rate, NSAIDs = non-steroidal anti-inflammatory drugs.

Results

Among the 4056 patients enrolled in the KCHF registry, 271 died during the index hospitalization. Among the 3758 patients who were discharged alive, we excluded 200 patients because of missing appetite data. We also excluded 57 patients due to missing follow-up data after discharge. Finally, the study population for the present analysis consisted of 3528 patients who were discharged alive with data on appetite and follow-up data. There were 405 patients (11.5%) with and 3123 patients (88.5%) without appetite loss at hospital discharge (Fig 1). Among 405 patients with appetite loss, 290 patients had mild appetite loss (8.3%) and 115 patients had moderate/severe appetite loss (3.2%) (Fig 1).

Fig 1

Study flowchart.

ADHF = acute decompensated heart failure, KCHF = Kyoto Congestive Heart Failure.

Baseline patient characteristics

Patients with appetite loss were older, more often female, and had a lower BMI than those without appetite loss (Table 1). Chronic kidney disease and dementia were more frequent in patients with appetite loss, whereas hypertension, diabetes, and current smoking were more frequent in those without appetite loss. Ambulatory patients were less frequent in the appetite loss group. LVEF was not significantly different between the two groups. BNP, creatinine, blood urea nitrogen, and CRP levels were significantly higher, whereas sodium and hemoglobin levels were significantly lower in the appetite loss group than in the no appetite loss group. Angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin II receptor blocker (ARB), mineralocorticoid receptor antagonist (MRA), and beta-blockers were less frequently prescribed, whereas pimobendane was prescribed more frequently in the appetite loss group than in the no appetite loss group. The differences in laboratory values at discharge were mostly consistent with those at admission, except for the sodium level. Residual edema was observed more often in the appetite loss group than in the no appetite loss group (Table 1).

Factors independently associated with appetite loss at discharge

In the multivariable logistic regression analysis, BMI < 22 kg/m2 (OR: 1.57, 95% CI: 1.11–2.24, P = 0.01), CRP >1.0mg/dL (OR: 1.49, 95%CI: 1.04–2.14, P = 0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99–6.22, P<0.001) were associated with an increased risk of appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39–0.83, P = 0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50–0.98, P = 0.04) were related to a decreased risk in the presence of appetite loss (Table 2). The characteristics of patients who did not use ACE-Is/ARB are shown in S1 Table.

Table 2

Factors associated with appetite loss at discharge.

		Univariate			Multivariable
	OR	95%CI	P value	OR	95%CI	P value
Age ≥80 years	1.72	1.39–2.13	<0.001	1.06	0.73–1.55	0.76
Men	1.43	1.17–1.77	<0.001	1.11	0.79–1.56	0.53
BMI <22 kg/m2	1.65	1.33–2.05	<0.001	1.57	1.11–2.24	0.01
Prior hospitalization due to HF	1.55	1.26–1.92	<0.001	1.14	0.82–1.61	0.43
Hypertension	0.70	0.56–0.88	0.002	0.77	0.53–1.10	0.15
Diabetes mellitus	0.77	0.61–0.96	0.018	1.34	0.92–1.95	0.13
Current smoking	0.53	0.36–0.79	0.001	0.50	0.24–1.03	0.06
Dementia	1.87	1.47–2.37	<0.001	1.20	0.80–1.79	0.37
Ambulatory	0.41	0.33–0.51	<0.001	0.57	0.39–0.83	0.004
BNP >200 pg/mL at discharge	1.50	1.13–1.98	<0.001	1.16	0.81–1.67	0.41
eGFR <30 mL/min/1.73m2 at discharge	1.76	1.41–2.19	<0.001	1.41	0.98–2.04	0.06
Anemia at discharge	1.69	1.31–2.17	0.006	1.27	0.85–1.91	0.24
C reactive protein >1.0 mg/dL at discharge	1.60	1.27–2.00	<0.001	1.49	1.04–2.14	0.03
Albumin<3.0mg/dL at discharge	1.82	1.41–2.33	<0.001	1.21	0.80–1.83	0.36
ACE-Is/ARBs at discharge	0.61	0.50–0.76	<0.001	0.70	0.50–0.98	0.04
Beta-blockers at discharge	0.78	0.63–0.97	0.02	0.92	0.65–1.30	0.63
Aspirin at discharge	0.73	0.58–0.91	0.005	0.69	0.48–0.99	0.047
Pimobendane at discharge	1.89	0.30–2.77	<0.001	1.38	0.77–2.48	0.28
Presence of edema at discharge	5.61	4.44–7.10	<0.001	4.30	2.99–6.22	<0.001

BMI = body mass index, ACE-I = angiotensin-converting enzyme inhibitor, ARB = angiotensin II receptor blocker, BNP = brain-type natriuretic peptide, eGFR = estimated glomerular filtration rate, CRP = C reactive protein.

One-year outcomes: Appetite loss vs. no appetite loss at discharge

The median length of the follow-up was 468 (IQR, 362 to 637) days, with a 95.8% follow-up rate at 1 year. The cumulative 1-year incidence of the primary outcome measure (all-cause death) was significantly higher in patients with appetite loss than in those without appetite loss (31.0% vs. 15.0%, P<0.001) (Fig 2A). The cumulative 1-year incidence of CV death, non-CV death, and HF hospitalization was also significantly higher in patients with appetite loss than in those without appetite loss (19.5% vs. 9.1%, P<0.001; 13.7% vs. 6.0%, P<0.001; and 27.5% vs. 23.5%, P = 0.02, respectively) (Fig 2B–2D). After adjusting for confounders, the excess risk of patients with appetite loss relative to those without appetite loss remained significant for all-cause death, CV death, and non-CV death but was no longer significant for HF hospitalization (Table 3).

Fig 2

Kaplan-Meier curves according to the presence or absence of appetite loss at discharge for (A) the primary outcome measure (all-cause death), (B) CV death, (C) non-CV death, and (D) HF hospitalization. HR, hazard ratio; CI, confidence interval; CV, cardiovascular; HF, heart failure.

Table 3

Clinical outcomes at 1-year.

	Appetite loss (+)		Appetite loss (-)
Outcome	N of patientswith event/N of patients at risk	Cumulative1-yearincidence	N of patientswith event/N of patients at risk	Cumulative1-yearincidence
						Unadjusted			Adjusted
					HR	95%CI	P-value	HR	95%CI	P-value
Primary outcome measure
All-cause death	122/405	31.0%	457/3123	15.0%	2.35	1.93–2.87	<0.001	1.63	1.29–2.07	<0.001
Secondary outcome measures
CV death	73/405	19.5%	274/3123	9.2%	2.31	1.78–2.99	<0.001	1.63	1.20–2.22	0.002
Non-CV death	48/405	13.7%	177/3123	6.0%	2.39	1.74–3.29	<0.001	1.59	1.08–2.34	0.02
HF hospitalization	97/405	27.5%	689/3123	23.5%	1.27	1.03–1.57	0.02	0.97	0.76–1.23	0.78

HR = hazard ratio, CI = confidence interval, CV = cardiovascular, HF = heart failure.

In an exploratory analysis, the cumulative 1-year incidence of all-cause death, and CV death was significantly higher in the moderate/severe appetite loss group than in the mild appetite loss group (37.9% vs. 27.8%, P = 0.02; and 28.1% vs. 15.5%, P = 0.002, respectively), whereas the cumulative 1-year incidence of non-CV death and HF hospitalization were not significantly different between the two groups (13.6% vs. 13.7%, P = 0.99; and 26.9% vs. 27.7%, P = 0.88, respectively) (S1A–S1D Fig). In the subgroup analysis, there was a significant interaction between the ambulatory status and the effect of appetite loss on the primary outcome measure (ambulatory: adjusted HR 2.15, 95%CI 1.59–2.90, P<0.001) and non-ambulatory: adjusted HR 1.36, 95%CI 0.94–1.96, P = 0.10, P interaction = 0.02). No interactions were observed for other subgroup factors (S2 Table).

Discussion

In the current study, 11.5% of patients complained appetite loss at discharge. Residual edema, ADL, nutritional status, inflammatory status, and certain types of medication were independently associated with appetite loss. BMI < 22 kg/m2, which reflects poor nutritional status, increased the risk of appetite loss incidence, whereas ambulatory status, which is related to higher activity, decreased the risk in the presence of appetite loss. Neither loss nor increase in appetite is common as a side effect of ACE-Is/ARBs, but the positive link between the absence of ACE-Is/ARB use and appetite loss is presumed to be the reflection of renal function and poor general condition of the patients with appetite loss.

Notably, more than 30% of these patients with appetite loss died within 1 year of hospital discharge. This is not surprising because appetite loss is associated not only with well-known prognostic factors in heart failure (such as serum albumin, and hemoglobin), but also with factors associated with frailty (cognitive dysfunction and ADL). Decreased serum albumin is not just a sign of nutritional status, but also reflect congestion and advanced pathological changes in the liver due to chronic liver congestion. Anemia in patients with heart failure, as well as hypoalbuminemia, is not only a reflection of nutritional status, but also a result of chronic inflammation caused by heart failure itself, concomitant renal dysfunction, reduced erythropoietin production and sensitivity, and suppression of hematopoietic stem cell function by ACE-Is and ARB.

Previous studies have revealed a close link between the nutritional status and the prognosis of patients with heart failure [1-3,26-29]. The presence of cachexia, frailty, and ADL has also been reported to be associated with prognosis in patients with heart failure [30-32]. In addition, low output due to heart failure leads to intestinal edema and dysfunction. Congestion and hypoalbuminemia due to heart failure also leads to intestinal edema and dysfunction, resulting in loss of appetite. The presence of appetite loss also reflects the severity of heart failure itself, and therefore should be associated with poor long-term outcomes.

In the exploratory analysis, the severity of appetite loss was also associated with all-cause and cardiac deaths. Appetite loss is a subjective symptom, but it is related to outcomes in a severity-dependent manner. The cause-effect relationship between appetite loss and poor clinical outcomes could not be determined because this was an observational study. Therefore, it is unclear whether the improvement in appetite loss is associated with an improvement in nutritional status and clinical outcomes. However, this result implies that appetite is a reliable prognostic marker, and if the patients cannot eat, it is possible that the patients have serious conditions associated with poor prognosis. The current guidelines mention frailty, cachexia, and sarcopenia, as well as iron deficiency [16]. Efficient caloric intake and nutrition supplementation are necessary to solve these problems [33], and it is also important to address loss of appetite. Recently, anamorelin has been used for cancer cachexia [34]. Anamorelin exerts its effects by acting on the ghrelin receptor, GHS-R1a [35]. GHS-R1a is distributed in many tissues and is involved in the release of growth hormone in the pituitary gland and the enhancement of appetite. Anamorelin may have muscle mass and weight gain effects by promoting GH secretion and increasing appetite through the activation of GHS-R1a [35,36]. Although anamorelin is contraindicated in patients with heart failure because of its negative effect on cardiac function, nutritional intervention as well as pharmaceutical intervention may be an option in the future.

Limitations

The current study has several limitations. First, this was an observational study; therefore, there might be the unmeasured confounders that affect the link between appetite loss and increased mortality. Second, appetite loss is a subjective measure, and there was no objective measure of appetite loss in this study. Third, there was no record of food intake; therefore, it was not possible to compare the actual calorie intake. Fourth, newly initiated medication during hospitalization may affect appetite; however, the appetite date was only available at discharge, and the association with these medications is unknown.

Conclusions

Loss of appetite at discharge is associated with worse 1-year mortality in patients with ADHF. Appetite is a simple, reliable, and useful subjective marker for risk stratification of patients with ADHF.

Kaplan-Meier curves according to the degree of appetite loss at discharge for (A) the primary outcome measure (all-cause death), (B) CV death, (C) non-CV death, and (D) HF hospitalization. HR = hazard ratio, CI = confidence interval, CV = cardiovascular, HF = heart failure.

(PDF)

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Patient characteristics without ACE-Is/ARB use.

(PDF)

Click here for additional data file.

Subgroup analysis for the effect of appetite loss on the primary outcome measure.

(PDF)

Click here for additional data file.

This contains the supplementary methods.

(PDF)

Click here for additional data file.

15 Nov 2021

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Reviewer #1: A paper of Yamamoto et al. presents results of an observational study which included over 3 thousand patients with acute heart failure. The study population and follow-up time (mean 1-2 years) are the great advantages of the study. Methods and results are clearly described. Unfortunately, discussion is very simplistic with only a superficial analysis of potential mechanisms linking appetite loss and heart failure. Moreover, Authors haven’t referred any original papers concerning the issue of appetite loss and anorexia/cachexia syndrome in heart failure (and in the past years there were at least few important papers published). First paragraph of the discussion is in the fact repeated results’ summary which, in my opinion, is needless.

Furthermore I have some minor objections:

1. Phrase “ambulatory status” in the abstract is unclear – did the Authors meant “ambulatory” vs “hospitalized” or NYHA class? Then in the result section again is an information that “Ambulatory patients were less frequent in the appetite loss group” – it should a status at hospital discharge so what is the “non-ambulatory status”? I think it should be defined

2. Where are the results of subgroup analysis depending on “activity of daily living”?

3. “Neither loss nor increase of appetite is common as a side effect of ACE-Is/ARBs, but the

positive link between the absence of ACE-Is/ARB use and appetite loss is presumed to be the

reflection of renal function and poor general conditions of the patients with appetite loss.” – there is not direct data presented in the study which could support the thesis

4. Decreased serum albumin and hemoglobin concentration are not just a sign of nutrition status but reflect advanced pathological changes in heart failure, including i.a. liver and renal failure, iron deficiency

Reviewer #2: This is a retrospective analysis from the Kyoto Congestive Heart Failure registry focusing on the prevalence and prognostic impact of appetite loss in 3,528 patients with acute heart failure. As one might expect, appetite loss at discharge was associated with worse clinical status and a worse 1-year outcome. The study is original in that it explores appetite loss in this setting. On the other hand, it has the limitations of a retrospective analysis on a non-dedicated database, namely the lack of relevant information such as food intake etc. Study limitations are correctly acknowledged by the Authors. Please find below some other comments.

Patients were not selected based on their cognitive status, and assessment of appetite loss (as well as its classification as mild, moderate or severe) relied exclusively on patient report. Food intake and calories per day could have been easily checked in hospitalized patients, and would have provided objective metrics for analysis.

Please specify more clearly what you mean by "ambulatory status" (patients treated with iv diuretics without hospitalization?)

Apart from medications at discharge, you should have considered also the start of drugs from admission to discharge, as starting multiple therapies could reduce patient appetite.

Table 2 reports only univariable predictors. Please provide the full list of variables evaluated as possible univariable predictors. It is important to understand if relevant variables such as the length of hospitalization were taken into account. The list of univariable predictors is rather short, with several arbitrarily dichotomized variables.

In the abstract, please specify the variables included in the multivariable model.

The approval numbers by the many centers (page 12) could be moved to the supplementary material.

The manuscript would benefit from linguistic revision.

**********

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Reviewer #1: Yes: Anna Drohomirecka

Reviewer #2: No

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25 Dec 2021

Reviewer #1: A paper of Yamamoto et al. presents results of an observational study which included over 3 thousand patients with acute heart failure. The study population and follow-up time (mean 1-2 years) are the great advantages of the study. Methods and results are clearly described. Unfortunately, discussion is very simplistic with only a superficial analysis of potential mechanisms linking appetite loss and heart failure.

Thank you so much for the important comment. Actually, the analysis is very simple in this study. KCHF study is not just focused on the nutrition and heart failure, therefore we didn’t collect many important factors, such as the change of body weight, or any objective evaluation measure about appetite loss (CNAQ-J, MNA etc.) and cannot draw any conclusion about the causal relationship between appetite, nutrition status, and prognosis. We would like to avoid overstating the result and just show that the patient with appetite loss at hospital discharge was associated with poor outcome. Based on this situation, we added several sentences in discussion part.

The current guidelines mention frailty, cachexia, and sarcopenia, as well as iron deficiency.12 Efficient caloric intake and nutrition supplementation is necessary to solve these problems, and it is also important to address loss of appetite. Recently, Anamorelin has been used for cancer cachexia. Anamorelin exerts its effects by acting on the ghrelin receptor, GHS-R1a. GHS-R1a is distributed in many tissues and is involved in the release of growth hormone in the pituitary gland and the enhancement of appetite. Anamorelin may have muscle mass and weight gain effects by promoting GH secretion and increasing appetite through activation of GHS-R1a. Although Anamorelin is contraindicated in heart failure patients because of its negative effect for cardiac function, pharmaceutical intervention as well as nutritional intervention may be an option in the future.

Moreover, Authors haven’t referred any original papers concerning the issue of appetite loss and anorexia/cachexia syndrome in heart failure (and in the past years there were at least few important papers published).

Thank you so much for your constructive comment. We added several references.

First paragraph of the discussion is in the fact repeated results’ summary which, in my opinion, is needless.

Thank you so much for the comment. We deleted summary in discussion.

1. Phrase “ambulatory status” in the abstract is unclear – did the Authors meant “ambulatory” vs “hospitalized” or NYHA class? Then in the result section again is an information that “Ambulatory patients were less frequent in the appetite loss group” – it should a status at hospital discharge so what is the “non-ambulatory status”? I think it should be defined.

Thank you so much for the comment. We defined ambulatory status as patients who can walk by themselves. In this study, we assessed patient’s ADL on four level: (1) ambulatory (patients who can walk by themselves), (2) use wheelchair (outdoor only), (3) use wheelchair (outdoor and indoor), (4) bedridden. “Ambulatory status” means patients with highest ADL level among them. We added definition in supplementary appendix.

2. Where are the results of subgroup analysis depending on “activity of daily living”?

Thank you so much for the comment. As mentioned above, “ambulatory” means ADL status. “ambulatory” vs “non-ambulatory” (the third in supplementary table 1) correspond the result of subgroup analysis depending on ADL.

3. “Neither loss nor increase of appetite is common as a side effect of ACE-Is/ARBs, but the positive link between the absence of ACE-Is/ARB use and appetite loss is presumed to be the reflection of renal function and poor general conditions of the patients with appetite loss.” – there is not direct data presented in the study which could support the thesis.

Thank you so much for the constructive comment. We evaluated whether general condition, including renal function is worse in patients without ACE-Is/ARB use. We have added the Characteristics of patients without ACE-Is/ARB use in the Supplementary Table 1.

Appetite loss (-) 　 　 　 Appetite loss (+)

ACE-I/ARB (+) ACE-I/ARB (-) P 　 ACE-I/ARB (+) ACE-I/ARB (-) P

Age 78 (69-85) 82 (74-87) <0.001 　 82 (73-87) 84 (78-89) 0.02

Age ≧80 843 (45.4) 725 (57.3) <0.001 　 111 (57.8) 146 (68.5) 0.03

Male 1098 (59.2) 663 (52.4) <0.001 　 97 (50.5) 95 (44.6) 0.23

BMI≦22 750 (41.8) 587 (49.2) <0.001 　 98 (54.8) 116 (59.5) 0.35

hx of HF 623 (33.9) 451 (36.3) 0.17 　 69 (38.1) 108 (51.7) 0.007

Anemia 1123 (60.5) 910 (72.1) <0.001 　 126 (66.6) 166 (77.9) 0.006

Alb<3.0mg/dL 189 (10.4) 188 (15.4) <0.001 　 34 (18.5) 40 (19.6) 0.78

eGFR<30 355 (19.1) 421 (33.3) <0.001 　 55 (28.7) 83 (39.2) 0.03

Na<135 177 (9.6) 171 (13.6) <0.001 　 21 (10.9) 39 (18.5) 0.03

CRP>1.0 369 (22.2) 339 (29.1) <0.001 　 79 (64.8) 105 (75.0) 0.07

HFrEF 769 (41.5) 383 (30.4) <0.001 　 79 (41.4) 63 (29.6) 0.01

Patients without ACE-I/ARB were older, had lower BMI and worse renal function compared to patients with ACE-I/ARB in both patients with and without appetite loss.

4. Decreased serum albumin and hemoglobin concentration are not just a sign of nutrition status but reflect advanced pathological changes in heart failure, including i.a. liver and renal failure, iron deficiency

Thank you so much for the comment. We agree with author’s comment. We added the sentence below in discussion part.

“Decreased serum albumin is not just a sign of nutrition status but reflect congestion and advanced pathological changes in liver due to chronic liver congestion. Anemia in patients with heart failure, as well as hypoalbuminemia, is not only a reflection of nutritional status, but also a result of chronic inflammation caused by heart failure itself, concomitant renal dysfunction and reduced erythropoietin production and sensitivity, as well as suppression of hematopoietic stem cell function by ACE inhibitors and angiotensin II receptor blockers.”

Reviewer #2: This is a retrospective analysis from the Kyoto Congestive Heart Failure registry focusing on the prevalence and prognostic impact of appetite loss in 3,528 patients with acute heart failure. As one might expect, appetite loss at discharge was associated with worse clinical status and a worse 1-year outcome. The study is original in that it explores appetite loss in this setting. On the other hand, it has the limitations of a retrospective analysis on a non-dedicated database, namely the lack of relevant information such as food intake etc. Study limitations are correctly acknowledged by the Authors. Please find below some other comments.

Patients were not selected based on their cognitive status, and assessment of appetite loss (as well as its classification as mild, moderate or severe) relied exclusively on patient report. Food intake and calories per day could have been easily checked in hospitalized patients, and would have provided objective metrics for analysis.

Thank you for the constructive comment. We would like to collect these quantitative data in next study.

Please specify more clearly what you mean by "ambulatory status" (patients treated with iv diuretics without hospitalization?)

Thank you for the comment. We defined ambulatory status as patients who can walk by themselves. In this study, we assessed patient’s ADL on four level: (1) ambulatory (patients who can walk by themselves), (2) use wheelchair (outdoor only), (3) use wheelchair (outdoor and indoor), (4) bedridden. “Ambulatory status” means patients with highest ADL level among them. We added definition in supplementary appendix.

Apart from medications at discharge, you should have considered also the start of drugs from admission to discharge, as starting multiple therapies could reduce patient appetite.

Thank you for pointing out important point. We added the sentence below in limitation part.

“Forth, newly initiated medication during hospitalization may affect appetite, however appetite date was only available at discharge, and the association with those medication is unknown.”

Table 2 reports only univariable predictors. Please provide the full list of variables evaluated as possible univariable predictors. It is important to understand if relevant variables such as the length of hospitalization were taken into account. The list of univariable predictors is rather short, with several arbitrarily dichotomized variables.

Thank you for the comment. We assessed clinical and laboratory data shown in Table 1, and choose 19 factors with P value < 0.1 by univariate analysis. We added the underlined part in method section.

A multivariable logistic regression model was developed to identify clinical characteristics, and laboratory data and medications at discharge that were independently associated with the presence of appetite loss using 19 factors with P value < 0.1 by univariate analysis extracted from the variables listed in Table 1.”

In the abstract, please specify the variables included in the multivariable model.

Thank you for the comment. We added the underlined part in abstract.

“In the multivariable logistic regression analysis using 19 clinical and laboratory factors with P value < 0.1 by univariate analysis, BMI…”

The approval numbers by the many centers (page 12) could be moved　to the supplementary material.

Thank you for the comment. We moved the individual approval numbers to supplementary appendix.

The manuscript would benefit from linguistic revision.

Thank you for the constructive comment. The revised manuscript has been edited by native speaker.

Submitted filename: rebuttal_appetite_1223.docx

Click here for additional data file.

13 Jan 2022

31 Jan 2022

Reviewer #1: The revised manuscript replies to most but not all comments of the previous review. Authors significantly improved the discussion section and clarified some ambiguities. Nevertheless, in my opinion, some parts still needs explanation or completion.

We appreciate the time and effort that you have dedicated to providing your valuable feedback on my manuscript. We revised the manuscript again according to your comments.

The definition of “ambulatory status” should be placed in the main text body not in the supplement.

Thank you so much for the comment. We moved the definition of “ambulatory status” in the supplement to main text.

A statement “However, there was no study focused on “appetite loss,” which is a subjective symptom in patients with heart failure. “ is untrue – there are studies concerned on appetite loss in patient with heart failure and Authors have been already asked to quote these in the discussion.

Thank you so much for the comment. Based on your comment, we have revised the sentence as follows.

P3 L15 Although in the past years there were at least few important papers published concerning the issue of appetite loss and anorexia/cachexia syndrome in heart failure [PMID: 9107242, PMID: 25704364, PMID: 34757487, PMID: 24347122, PMID: 26865478], there is still scarcity in the studies focused on “appetite loss,” a subjective symptom in patients with heart failure [PMID: 24347122, PMID: 26865478].

There are sentences which need rephrasing:

- “We assessed 3528 patients who were alive at discharge for whom appetite and had follow-up data were available.”

Thank you so much for the comment. Based on your comment, we have revised the sentence as follows.

P2 L7 We assessed 3528 patients alive at discharge, and for whom appetite and follow-up data were available.

- “In the multivariable logistic regression analysis using 19 clinical and laboratory factors with P value < 0.1 by univariate analysis, BMI < 22 kg/m2 (odds ratio (OR): 1.57, 95% confidence interval (CI): 1.11-2.24, P=0.01), CRP >1.0mg/dL (OR: 1.49, 95%CI: 1.04-2.14, P=0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99-6.22, P<0.001) were positively associated with appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39-0.83, P=0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50-0.99, P=0.04) were negatively associated with appetite loss.” Phrase “positive/negative association” when odds ratio are used is a little bit unfortunate because it is not a correlation but risk increase/decrease.

Thank you so much for the comment. Based on your comment, we have revised the sentence as follows.

P2 L9 In the multivariable logistic regression analysis using 19 clinical and laboratory factors with P value < 0.1 by univariate analysis, BMI < 22 kg/m2 (odds ratio (OR): 1.57, 95% confidence interval (CI): 1.11-2.24, P=0.01), CRP >1.0mg/dL (OR: 1.49, 95%CI: 1.04-2.14, P=0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99-6.22, P<0.001) were associated with an increased risk of appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39-0.83, P=0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50-0.99, P=0.04) were related to decrease risk in the presence of appetite loss.

- “The details have been previously descrived.” – please correct a typing mistake

Thank you so much for the comment. Based on your comment, we have revised the sentence as follows.

P5 L9 The details have been previously described.

- “When we consider the cause of appetite loss, this result is clinically important, because there is no argument about the association between the amount of activity, nutritional status, and the presence of appetite loss.” – the sentence is either unclear or false. There are many links between amount of activity, nutritional status and appetite loss.

Thank you so much for the comment. As you pointed out, we also think there are many links between these factors and appetite loss and the result of this study are reasonable. We revised the sentence more simply.

P19 L14 When we consider the cause of appetite loss, there is no argument about the association between the amount of activity, nutritional status, and the presence of appetite loss.

- “In addition, low output due to heart failure leads intestinal edema and dysfunction.

Congestion and hypoalbuminemia due to heart failure also leads intestinal edema and

dysfunction, resulting in loss of appetite.” or “leads to” ?

Thank you so much for the comment. Based on your comment, we have revised the sentence as follows.

P20L5 In addition, low output due to heart failure leads to intestinal edema and dysfunction. Congestion and hypoalbuminemia due to heart failure also leads to intestinal edema and dysfunction, resulting in loss of appetite.

Submitted filename: comment for reviewer_R2_final.docx

Click here for additional data file.

18 Mar 2022

18 Mar 2022

Response:

We thank the reviewer for detailed assessment and positive comments. We have revised the manuscript according to your suggestions.

Reviewer #1: The majority of concerns raised in the previous review were addressed. However, there are a few questions left.

I still have doubts about the following conclusion:

“When we consider the cause of appetite loss, because there is no argument about the association between the amount of activity, nutritional status, and the presence of appetite loss.”

It stands in the opposition to the results: BMI < 22 kg/m2 increased the risk of appetite loss incidence (OR: 1.57, 95% CI: 1.11-2.24, P=0.01), whereas ambulatory status (OR: 0.57, 95% CI: 0.39-0.83, P=0.004) decreased. BMI reflect nutritional status, ambulatory status is related to higher activity.

Response:

Thank you for the important comments. As you pointed out, poor nutritional status increased the risk of appetite loss incidence, whereas higher activity decreased the risk of appetite loss incidence. We have revised the manuscript as follows:

“BMI < 22 kg/m2, which reflects poor nutritional status, increased the risk of appetite loss incidence, whereas ambulatory status, which is related to higher activity, decreased the risk in the presence of appetite loss.” (Page 20, Lines 4-6)

Authors still used the phrase “positively/negatively associated” in the context of risk assessment:

“In the multivariable logistic regression analysis, BMI < 22 kg/m2 (OR: 1.57, 95% CI: 1.11-

2.24, P=0.01), CRP > 1.0mg/dL (OR: 1.49, 95% CI: 1.04-2.14, P=0.03), and the presence of edema at discharge (OR: 4.30, 95% CI: 12.99-6.22, P<0.001) were positively associated with appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95% CI: 0.39-0.83, P=0.004) and the use of ACE-I/ARB (OR:0.70, 95% CI: 0.50-0.99, P=0.04) were negatively associated with appetite loss (Table 2).” (page 14)

Response:

We appreciate your comments. We have deleted the phrases “positively/negatively associated”. We have changed these as follows:

“In the multivariable logistic regression analysis, BMI < 22 kg/m2 (OR: 1.57, 95% CI: 1.11-2.24, P=0.01), CRP >1.0mg/dL (OR: 1.49, 95%CI: 1.04-2.14, P=0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99-6.22, P<0.001) were associated with an increased risk of appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39-0.83, P=0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50-0.98, P=0.04) were related to a decreased risk in the presence of appetite loss (Table 2)”. (Page 14 Lines 2-7)

There is a typing mistake in the abstract:

“were related to decrease risk in the presence of appetite loss” instead of: “were related to decreased risk in the presence of appetite loss

Response:

We have corrected the typing mistake. We appreciate your carful assessment.

Submitted filename: Response appetite_220319.docx

Click here for additional data file.

7 Apr 2022

Appetite Loss at Discharge from Acute Decompensated Heart Failure: Observation from KCHF registry

PONE-D-21-32941R3

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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Reviewer #1: Yes

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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Congratulations to Authors on their work!

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Reviewer #1: Yes: Anna Drohomirecka

28 Apr 2022

PONE-D-21-32941R3

Appetite Loss at Discharge from Acute Decompensated Heart Failure: Observation from KCHF registry

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