Prognostic Value of Rising Serum Albumin During Hospitalization in Patients With Acute Heart Failure

Accepted Manuscript Prognostic Value of Rising Serum Albumin during Hospitalization in Patients with Acute Heart Failure Hiroyuki Nakayama, MD, Satoshi Koyama, MD, Takashi Kuragaichi, MD, Masayuki Shiba, MD, Hisayoshi Fujiwara, MD, PhD, Yoshiki Takatsu, MD, PhD, Yukihito Sato, MD, PhD PII:

S0002-9149(16)30152-7

DOI:

10.1016/j.amjcard.2016.01.030

Reference:

AJC 21676

To appear in:

The American Journal of Cardiology

Received Date: 3 October 2015 Revised Date:

21 January 2016

Accepted Date: 22 January 2016

Please cite this article as: Nakayama H, Koyama S, Kuragaichi T, Shiba M, Fujiwara H, Takatsu Y, Sato Y, Prognostic Value of Rising Serum Albumin during Hospitalization in Patients with Acute Heart Failure, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.01.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Prognostic Value of Rising Serum Albumin during Hospitalization in Patients with Acute Heart Failure

Hiroyuki Nakayama, MD1, Satoshi Koyama, MD1, Takashi Kuragaichi, MD1, Masayuki

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Shiba, MD1, Hisayoshi Fujiwara, MD, PhD1, Yoshiki Takatsu, MD, PhD1, and Yukihito Sato, MD, PhD1

Department of Cardiology, Hyogo Prefectural Amagasaki General Medical Center,

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Higashinaniwa 2-17-77, Amagasaki, Hyogo, 660-8550, Japan

Article Short Title: Serum albumin change in patients with acute heart failure

Address for correspondence and reprints

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Hiroyuki Nakayama, MD

Department of Cardiology, Hyogo Prefectural Amagasaki General Medical Center Higashinaniwa 2-17-77, Amagasaki, Hyogo, 660-8550, Japan

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Tel: 06-6480-7000

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Fax: 06-6480-7721

E-mail: [email protected]

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ACCEPTED MANUSCRIPT Abstract Hypoalbuminemia is an important predictor of a poor long-term prognosis in acute heart failure (AHF). However, changes in serum albumin levels in AHF have not been described to date. Therefore, we investigated the changes in serum albumin levels in patients hospitalized

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for AHF. This observational study included 115 consecutive patients admitted with AHF. Serum albumin was measured on days 1, 2, 4, and 7 of their hospitalization, and the changes in its levels were assessed. Cox multivariate analysis was used to compare the long-term

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mortality and readmission rate between two groups defined according to whether their serum albumin changes showed a rising pattern (serum albumin level increased from day 2 to day 7)

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or not. The mean serum albumin levels were 3.51 mg/dL on day 1, 3.21 mg/dL on day 2, 3.23 mg/dL on day 4, and 3.35 mg/dL on day 7 (P < 0.001 by MANOVA). The rising pattern group including sixty-six patients (60.6%) was independently associated with a lower mortality and readmission rate (hazard ratios 0.450 and 0.522; P = 0.01 and 0.02,

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respectively). Furthermore, based on multiple linear regression analysis, the changes in hemoglobin and C-reactive protein levels during days 1 to 7 were independently correlated with the changes in serum albumin levels over the same period. In conclusion, a rising pattern

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of serum albumin change in a patient with AHF was correlated with a good long-term

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prognosis. Furthermore, the change in serum albumin levels was also associated with changes in cachectic factors.

Key words: acute heart failure, serum albumin, hemoglobin, C-reactive protein

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ACCEPTED MANUSCRIPT Introduction The correlation between serum albumin and heart failure has recently been emphasized. Hypoalbuminemia is associated with a poor prognosis in patients with chronic heart failure1)8)

. The half-life of serum albumin is shortened to about 9 days during the acute phase of a

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severe illness9)10). Serum albumin is a biomarker of nutritional state; therefore,

hypoalbuminemia is associated with prolonged malnutrition11). The correlation between

hypoalbuminemia and malnutrition in patients with acute heart failure (AHF) is, however,

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controversial. This is because serum albumin can be affected by several factors apart from the nutritional state, such as inflammation, accelerated metabolism, impaired synthesis, enteric or

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renal losses, and hemodilution12). A recent study1) found that malnutrition and inflammatory activations were important etiologic factors associated with hypoalbuminemia in AHF. These previous studies demonstrated a significant correlation between a single measurement of serum albumin and prognosis in AHF patients. However, it is also necessary to assess the

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changes in serum albumin during hospitalization when considering therapeutic interventions such as nutritional support. Furthermore hypoalbuminemia is one of cachectic abnormalities including increased levels of inflammatory markers such as C-reactive protein (CRP) and IL-

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6, and anemia13). Chronic heart failure is a common cause of cachexia, and patients with

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cachexia have a poor prognosis14). However the value of these biochemical markers in AHF is unknown. Methods

This was a single-center, observational study. The study was approved by the ethics committee of our institution. Between April 2009 and December 2011, we enrolled 115 consecutive patients aged >18 years who presented to our hospital with AHF and were diagnosed by a cardiologist, based on physical examination, chest radiograph, laboratory tests, and echocardiography, according to the American Heart Association guidelines. The

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ACCEPTED MANUSCRIPT patients received standard HF therapy, including noninvasive positive-pressure ventilation, vasodilators, diuretics, and catecholamines. Presenting with acute myocardial infarction, hypotension requiring fluid replacement or continuous infusions of norepinephrine, overt infection, a history of dialysis, or the need for a ventricular assist device or mechanical

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ventilation were grounds for exclusion from this study. To preserve the integrity of the data and expedite the handling and storage of samples collected, we excluded patients admitted between 5:00 pm and 9:00 am, on the weekends or holidays, as described previously15).

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The patients underwent a review of their medical history and drug therapy at admission. Body height and weight, systemic blood pressure, and heart rate were recorded throughout

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the course of treatment. Left-ventricular ejection fraction was measured by using ventriculography or echocardiography and calculated using the modified 2-dimensional Simpson method or the Teichholz formula.

Blood samples were collected ≤6 hours after the patient’s admission to the hospital. The

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day-2 samples were collected on the day following the admission day, the day-4 samples were collected between day 3 and day 5, and the day-7 samples were collected between day 6 and day 8 of hospitalization, depending on the day of the week on which the patient was

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admitted, to guarantee proper storage of the samples, as mentioned earlier. Because the

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equation used to estimate the glomerular filtration rate in Western countries might not be applicable to Asian patients, we used recently published equations for Japanese men (194 × serum creatinine − 1.094 × age − 0.287) and women (194 × serum creatinine − 1.094 × age − 0.287 × 0.739). NT-proBNP was measured using an Elecsys 2010 system (Roche Diagnostics, Tokyo, Japan). All study procedures were in compliance with the principles outlined in the Declaration of Helsinki and the institutional guidelines of Hyogo Prefectural Amagasaki Hospital. The authors had full access to and take responsibility for the integrity of the data. Continuous variables are presented as mean ± SD and categorical variables as

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ACCEPTED MANUSCRIPT percentages. The fit to the normal distribution of quantitative variables was assessed using the Shapiro–Wilk test. The differences in the mean serum albumin levels on days 1, 2, 4, and 7 were examined by using the paired t-test and multivariate analysis of variance. All-cause mortalities of early (in hospital) and long term were assessed. We checked long-

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term mortality in October 2015, 4 years after the last patient was discharged, by phone

whether the patients who we were unable to come for follow up visits were alive or not. We were unable to reach one patient by phone. We also assessed readmissions caused by heart

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failure. The 18 patients who either underwent a surgical operation (N = 5) or could not be followed up (N = 13) were excluded. We divided the patients into two groups according to

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whether their serum albumin changes had shown a rising pattern (serum albumin level increased from days 2 to 7) or not (serum albumin level decreased or did not change from days 2 to 7). This grouping was only focus on the values of serum albumin on days 2 and 7, therefore the values of serum albumin on days 1 and 4 had no contribution to these groups.

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For comparisons between groups, the chi-square test was used for qualitative variables, while the Student t-test and Wilcoxon rank sum were used for parametric and nonparametric quantitative variables, respectively. Kaplan–Meier survival curves were derived for the

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groups and were then compared using the log-rank test. To assess whether a change in serum

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albumin was an independent predictor of mortality and readmission, multivariate analysis was performed using the Cox regression model. Factors that showed significant prognostic influence on bivariate analyses (P < 0.05) were included, together with age and female sex. The results are given as hazard ratios (HRs) and 95% confidence intervals (CIs). We evaluated the correlation between the changes in albumin level and baseline characteristics, changes in body weight, systolic blood pressure, hemoglobin, bilirubin, aspartate transaminase, BUN, creatinine, estimated glomerular filtration rate (eGFR), CRP, and NT-proBNP by simple linear regression analyses. As the changes in creatinine and NT-

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ACCEPTED MANUSCRIPT proBNP were nonparametric quantitative variables, these variables were log transformed for analysis. Factors with a probability value of ≤0.05 on bivariate regression analyses were included in the multivariate linear regression analysis, together with age and female sex. The results are expressed as correlation coefficients.

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All statistical analyses were performed using the JMP software, version 11.0 (SAS Corporation, Cary, NC). Results

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The baseline characteristics of the patients in this study are shown in Table 1. The mean serum albumin levels were 3.52 mg/dL on day 1, 3.22 mg/dL on day 2, 3.23 mg/dL on day 4,

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and 3.35 mg/dL on day 7 (Figure 1). This change was statistically significant by paired t-tests comparing day-to-day changes (P < 0.0001), whereas the change from day 2 to day 4 was not significant (P = 0.73).

During hospitalization, the serum albumin levels followed a rising pattern in 66 patients

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(61%), whereas the remaining 49 patients showed either a decrease or no change. The baseline characteristics of each group are shown in Table 2. Four patients died of heart failure in hospital, and there is no significant difference between 2 groups (rising pattern group vs

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non-rising pattern group, 3.0% vs 4.6%, P=0.65). During the follow-up period (median 1111

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days, interquartile range 559–1460 days), 58 patients died and 53 patients were readmitted to hospital for the management of worsening heart failure. 10 patients died of heart failure, 8 of pneumonia, and 7 of cancer; 7 patients suddenly died of unknown causes. Figure 2 and 3 show the Kaplan–Meier survival curves of free from all-cause death and hospital readmission for both the rising and the non-rising pattern groups. The curves diverged from about 350 days after their admission. The multivariate Cox regression analysis indicated that the rising serum albumin pattern was independently correlated with a good prognosis (Table 3 and Supplement 1).

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ACCEPTED MANUSCRIPT On bivariate analyses, the changes in systolic blood pressure, hemoglobin, log (bilirubin), and urine albumin/creatinine ratio from days 1 to 4 were positively correlated, while ischemic heart disease was negatively correlated with the serum albumin change over the same period. On multivariate analysis, the changes in hemoglobin, log (bilirubin) and urine

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albumin/creatinine ratio were independently correlated (Supplement 2). On bivariate

analyses, the changes in systolic blood pressure and hemoglobin from days 1 to 7 were

positively correlated, while the changes in body weight and CRP from days 1 to 7 were

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negatively correlated with the serum albumin change over the same period. On multivariate analysis, the changes in hemoglobin and CRP were independently correlated (Supplement 3).

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Discussion

This study showed that changes in serum albumin levels in patients with AHF during hospitalization are specific and haves a long term prognostic value. To the best of our knowledge, this is the first report on the prognostic value of changes in serum albumin levels

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in patients with AHF. We assessed the association of day-to-day serum albumin changes with prognosis and found that the change from day 2 to day 7 had the best prognostic value (Supplement 4). The changes in serum albumin levels does not indicate short term prognostic

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value in this study, but a recent study1) showed an independent association of hypoalbuminemia with short term prognosis. Therefore, we need more cases to confirm this

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result. Several remarkable recent studies1)-8) have shown that hypoalbuminemia is an independent predictor of mortality in patients with acute or chronic heart failure. However, those studies did not report changes in serum albumin levels after hospitalization. Although the prognostic finding of hypoalbuminemia is quite helpful in clinical practice, our findings show that serum albumin changes can be of further value. This increases the possibility of improving serum albumin levels on day 7 by using therapeutic interventions, such as proper medication for AHF, nutrition support for

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ACCEPTED MANUSCRIPT malnutrition, and physical rehabilitation for muscle weakness during hospitalization. The relationship between malnutrition and hypoalbuminemia among patients with AHF is uncertain, but a recent study1) indicated that malnutrition and inflammatory activation could contribute to the etiology of hypoalbuminemia in patients with AHF. Therapy with

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angiotensin II receptor blockers has been shown to decrease CRP levels compared to

placebo16). This might suggest that the renin–angiotensin–aldosterone system (RAAS)

contributes to the inflammation in HF and that RAAS inhibitors could reduce inflammatory

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activation response in patients with HF. Alternatively, diuretics have been shown to reduce the permeability of capillary vessels to albumin. Regarding nutrition support, the PICNIC

HF who are malnourished.

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study17) clarifies the prognostic impact of nutritional intervention in hospitalized patients with

In this study, we demonstrated specific changes in serum albumin levels, decreasing from day 1 to day 2, and increasing from day 4 to day 7. The decrease in the levels could be caused

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by several factors, such as hypercatabolism, increased permeability of capillary vessels, hemodilution18), and liver dysfunction. Changes in the levels from day 1 to day 4 showed a significant positive correlation with changes in log (bilirubin) and the urine

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albumin/creatinine ratio (Table 5). This indicated that decrease in the serum albumin levels

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might be correlated with liver function and urine loss. However, the mechanism of the serum albumin dip is unclear because these three parameters changed proportionally in our study. Changes in serum albumin levels from day 1 to day 7 were significantly correlated with changes in hemoglobin and CRP. Hemoglobin in patients with AHF is affected by several factors, such as malnutrition, erythropoietin deficiency, or inefficiency caused by inflammation, hemodilution, and occult gastrointestinal blood loss19)20), all of which may also affect serum albumin levels. In this study, changes in hemoglobin levels were also significantly correlated with those in serum albumin levels changes from day 1 to day 4.

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ACCEPTED MANUSCRIPT However, hemoglobin as well as serum albumin levels did not show the dipping pattern during days 1 to 4 (Supplement 5). This might be because the half-life of hemoglobin (about 120 days) is longer than that of serum albumin. CRP is one of the acute phase reactants, which changes inversely with serum albumin during the acute phase of illness21).

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Furthermore, CRP levels are elevated in heart failure; higher levels are associated with more severe heart failure and are independently associated with mortality and morbidity16). These results indicate that inflammation, which results in increased CRP levels, could be one of the

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reasons for the dip in serum albumin levels.

Serum albumin, hemoglobin, and CRP are cachectic biomarkers13); therefore, these

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correlations indicate that these biomarkers could be affected by mechanisms similar to chronic heart failure, such as malnutrition, inflammation, and anabolic deficiency. Our study has some limitations. This study was conducted at a single center, and the sample size was small. Therefore, our findings need to be confirmed in a larger, well-

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designed study. Furthermore, the half-life of serum albumin might be too long to evaluate the acute phase status. However, serum albumin has a potential advantage that it can be easily measured and is used worldwide.

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Acknowledgements

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We are deeply grateful to Drs Taishi Kobayashi, Syunsuke Saga, Rei Fukuhara, Kazuyasu Yoshitani, Ryoji Taniguchi, Masanao Toma, and Tadashi Miyamoto whose enlightening opinions have been most helpful throughout the period of this study. Sources of Funding

This study was supported by unrestricted institutional funds. Disclosures The authors have no conflicts of interest to report. 9

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Wolfe R, Anker SD. Cachexia: a new definition. Clin Nutr 2008;27:793-799. 14. Anker SD, Steinborn W, Strassburg S. Cardiac cachexia. Ann Med 2004;36:518-529. 15. Koyama S, Sato Y, Tanada Y, Fujiwara H, Takatsu Y. Early evolution and correlates

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2005;112:1428-1434. 17. Antonio L. Gámez-López, Juan L. Bonilla-Palomas, Manuel Anguita-Sánchez, Mirian Moreno-Conde, Cristina López-Ibáñez, Rosa Alhambra-Expósito, Juan C. CastilloDomínguez, Antonia Villar-Ráez, José Suárez de Lezo. Rationale and Design of

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ACCEPTED MANUSCRIPT Figure Legends Figure 1. Serum albumin means in patients with acute heart failure during hospitalization was decreasing from day 1 to day 2, and increasing from day 4 to day 7. This change was

MANOVA=multivariate analysis of variance

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statistically significant by MANOVA (P < 0.0001)

Figure 2. Kaplan-Meier curves of free from all-cause death for the rising or non-rising pattern

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groups. The rising pattern group had significantly better prognosis than non-rising pattern

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group.

Figure 3. Kaplan-Meier curves of free from readmission for the rising or non-rising pattern groups. The rising pattern group had significantly better prognosis than non-rising pattern

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group.

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74.2 ±2.0

Women

57(51%)

Coronary heart disease

39(34%)

Diabetes mellitus

44(38%)

Atrial fibrillation

59(51%)

Drug therapy at admission

Beta-adrenergic blocker

59(51%)

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Renin-angiotensin-aldosterone axis antagonist

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Age (years)

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Table 1. Baseline characteristics (n=115)

52(43%)

Diuretic

76(66%)

Body mass index on day 10 (kg/m2)

59.5±2.8

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Body weight on day 1 (kg) Day 1

24.3±0.9

138.8±4.9

Diastolic blood pressure (mmHg)

79.5±3.4

Heart rate (beats per minute)

82.0±4.0

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Systolic blood pressure (mmHg)

Left-ventricular ejection fraction (%)

50.0±3.4

Patients with ejection fraction>45%

66(58%)

Hemoglobin (g/dL)

11.3±0.4

Sodium (mEq/L)

139.5±0.8

Albumin (mg/dL)

3.53±0.09

Blood urea nitrogen (mg/dL)

26.9±2.6

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1.36±0.16

Estimated glomerular filtration rate (mL/min per 1.73 m2)

47.3±4.2

Total bilirubin (mg/dL)

1.03±0.18

NT-pro b-type natriuretic peptide (pg/ml)

9859±3079

C-reactive protein (mg/dL)

0.74±0.31

Aspartate aminotransferase (IU/L)

46.5±19.5

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Values are means±SD or numbers(%) of observations.

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Creatinine (mg/dL)

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ACCEPTED MANUSCRIPT Table 2. Baseline characteristics in patients grouped according to rising or non-rising pattern of serum albumin change during hospitalization. Non-rising pattern

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Age (years)

72.7±2.7

76.5 ±3.4

0.05

Women

31(47%)

23(53%)

0.50

Coronary heart disease

22(35%)

16(37%)

0.68

Diabetes mellitus

21(32%)

21(49%)

0.07

Atrial fibrillation

34(52%)

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Rising pattern

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Drug therapy at admission

23(53%)

0.84

Renin-angiotensin-aldosterone axis antagonist

32(48%)

24(56%)

0,45

Beta-adrenergic blocker

23(35%)

22(51%)

0.09

42(64%)

28(65%)

0.87

24.0±1.1

24.8±1.4

0.35

59.2±3.7

60.3±4.7

0.78

Systolic blood pressure (mmHg)

138±6

142±8

0.45

Diastolic blood pressure (mmHg)

82±4

78±6

0.26

Heart rate (beats per minute)

85±5

79±7

0.35

Left-ventricular ejection fraction (%)

48.6±4.5

52.3±5.5

0.26

Patients with ejection fraction>45%

28(65%)

45(54%)

0.32

Hemoglobin (g/dL)

11..5±0.3

11.2±0.6

0.48

Sodium (mEq/L)

139.8±1.0

138.9±1.3

0.22

Albumin (mg/dL)

3.53±0.14

3.52±0.12

0.91

Diuretic

Body weight on day 1 (kg)

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Day 1

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Body mass index on day 10 (kg/m2)

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ACCEPTED MANUSCRIPT 25.1±3.5

30.0±4.3

0.03

Creatinine (mg/dL)

1.27±0.22

1.50±0.27

0.03

Estimated glomerular filtration rate (mL/min per 1.73 m2)

50.8±5.6

42.9±6.9

0.03

Total bilirubin (mg/dL)

1.03±0.24

1.09±0.29

0.69

NT-pro b-type natriuretic peptide (pg/ml)

9188±4133

C-reactive protein (mg/dL)

0.74±0.27

Aspartate aminotransferase (IU/L)

53.1±26.5

Urine albumin/creatinine ratio (mg/gCr)

555±273

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Blood urea nitrogen (mg/dL)

0.67

0.79±0.38

0.10

39.8±32.8

0.56

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11406±5120

0.37

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397±220

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Values are means±SD or numbers(%) of observations.

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ACCEPTED MANUSCRIPT Table 3. Cox regression analysis: Variables independently associated with free from all-cause death. Bivariable

P

Multivariable

Analysis

Analysis

Hazard ratio［ ［95% CI］ ］

Hazard ratio［ ［95% CI］ ］

P

1.069［1.029-1.117］

<0.001

1.041［0.999-1.089］

0.05

Systolic blood pressure on

0.986［0.974-0.998］

0.02

0.985［0.972-0.998］

0.02

Hemoglobin

0.853［0.730-0.989］

0.03

Log(total bilirubin)

1.827［1.105-2.944］

0.01

2.106［1.247-3.450］

<0.01

Estimated glomerular

0.984［0.979-0.997］

0.01

0.991［0.972-1.008］

0.29

0.394［0.208-0.729］

<0.01

0.450［0.229-0.866］

0.01

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CI, confidence interval

0.24

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filtration rate Rising pattern group

0.875［0.696-1.094］

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Blood chemistry on day 1

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day 1

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Age

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ACCEPTED MANUSCRIPT Figure 1.

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3.9

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3.5 3.3 3.1

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Mean Serum albumin(mg/dL)

3.7

2.9

MANOVA P<0.001

2.7 2.5

day 2

day 4

day 7

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day 1

1

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Figure 2.

1

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Figure 3.

1