Accepted Manuscript

Longitudinal Trends, Hemodynamic Profiles, and Prognostic Value of Abnormal LiverFunction Tests in Patients with Acute Decompensated Heart Failure: an Analysis ofthe ESCAPE Trial

Michael Scholfield , MD Matthew B. Schabath , PhD Maya Guglin , MD, PhD

PII: S1071-9164(14)00205-X

DOI: 10.1016/j.cardfail.2014.05.001

Reference: YJCAF 3297

To appear in: Journal of Cardiac Failure

Received Date: 24 October 2013

Revised Date: 6 May 2014

Accepted Date: 8 May 2014

Please cite this article as: Scholfield M, Schabath MB, Guglin M, Longitudinal Trends, HemodynamicProfiles, and Prognostic Value of Abnormal Liver Function Tests in Patients with Acute DecompensatedHeart Failure: an Analysis of the ESCAPE Trial, Journal of Cardiac Failure (2014), doi: 10.1016/j.cardfail.2014.05.001.

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Longitudinal Trends, Hemodynamic Profiles, and Prognostic Value of Abnormal Liver Function Tests in

Patients with Acute Decompensated Heart Failure: an Analysis of the ESCAPE Trial

Michael Scholfield, MD1*; Matthew B. Schabath, PhD

2; Maya Guglin, MD, PhD

1

1Department of Cardiology, University of South Florida, Tampa, FL;

2Department of Cancer Epidemiology, H.

Lee Moffitt Cancer Center and Research Institute, Tampa, FL

*Corresponding Author: Michael Scholfield, MD

University of South Florida

2 Tampa Circle, 5th

Floor Cardiology

Tampa, FL 33612

E-mail: mscholfi@health.usf.edu

813-361-7622

Fax: 813-259-0665

Running head: LFTs in Acutely Decompensated Heart Failure

Abstract Word Count: 230 words

Text Word Count: 6161 words

Tables and Figures: 4 Tables and 3 Figures

Key Words: Albumin, Bilirubin, Creatinine, MELD

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Introduction: This study analyzed liver function abnormalities in heart failure patients admitted with severe

acute decompensated heart failure (ADHF).

Methods: A post hoc analysis was conducted using data from the Evaluation Study of Congestive Heart Failure

and Pulmonary Artery Catheterization Effectiveness (ESCAPE). Liver function tests (LFTs) were measured at

seven time-points from baseline, discharge, and up to six months follow-up. Survival analyses were utilized to

assess the association between admission model of end-stage liver disease-excluding INR (MELD-XI) scores

and patient outcome.

Results: There was a high prevalence of abnormal baseline (admission) LFTs (albumin 23.8%, aspartate

transaminase 23.5%, alanine transaminase 23.8%, and total bilirubin 36.1%). The percentage of patients with

abnormal LFTs decreased significantly from baseline to six months follow-up. When mean hemodynamic

profiles were compared in patients with abnormal vs. normal LFTs, elevated total bilirubin was associated with

a significantly lower cardiac index (1.80 vs. 2.1; P<0.001) and higher central venous pressure (14.2 vs 12.0;

P=0.03). Multivariable analyses revealed that patients with elevated MELD-XI scores (≥ 16.8) had a 2-fold (HR

= 2.06; 95% CI 1.05 – 4.03) increased risk of death, re-hospitalization, or transplant after adjusting for baseline

LFTs, age, gender, race, BMI, diabetes, and systolic blood pressure.

Conclusions: Abnormal LFTs are common in the ADHF population and are a dynamic marker of an impaired

hemodynamic state. Elevated MELD-XI scores are associated with poor outcomes among patients admitted

with ADHF.

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Introduction

Most of what is understood about abnormal liver function tests (LFTs) in heart failure (HF) derives from the

stable chronic HF patient population (1, 2). Recent studies have analyzed abnormal LFTs in the acutely

decompensated heart failure (ADHF) patient population. Abnormalities in LFTs are common, occurring in

upwards to 70% of these patients, and show a vastly different distribution than those in stable HF (3, 4).

Presently little is known about longitudinal trends of LFTs in patients admitted with, and treated for ADHF.

Abnormal LFTs in HF patients occur from two hemodynamic states. A decreased cardiac output state

leading to impaired organ perfusion is associated with acute centrilobular hepatocellular damage, ischemic

hepatic injury, and necrosis. Additionally, elevated right atrial filling pressures may lead to congestive hepatic

injury and a pathologic finding described as “nutmeg liver”(5). There is growing evidence that individual

biochemical markers correlate with various hemodynamic states and the degree of hepatic injury depends on

the contribution from congestion verses poor perfusion. There is substantial variability between studies, and it

is still unclear if elevated liver enzymes in individuals with HF are surrogates of hemodynamics.

It is generally accepted that certain LFTs, namely total bilirubin, are strong independent predictors of

increased risk of death and poor outcomes (1, 2, 4). This parallels what we understand about hepatorenal

syndrome and renal dysfunction predicting multi-system involvement in HF. Multiple recent studies have

used the Model of End-stage Liver Dysfunction (MELD) scoring model, which combines markers of renal and

liver function to predict outcomes in HF patients and have found it to be a powerful predictive tool.

Traditionally, the MELD score is used in predicting mortality and morbidity in cirrhotic patients undergoing

surgery or liver transplant. Recently Kim et al. (6) applied MELD scoring to evaluate urgency for heart

transplant in ambulatory HF patients. A modified MELD score excluding INR calculated as: [MELD-XI = (5.11 *

Ln total bilirubin) + (11.76 * Ln creatinine) + 9.44], has been standardized owing to the large number patients

on anticoagulation, and is highly predictive in the HF population (7, 8). MELD-XI has been shown to predict the

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survival following left ventricular assist device implantation and is emerging as a highly predictive composite

score for multi-system dysfunction in heart failure (9).

The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness

(ESCAPE) trial collected longitudinal LFTs from admission (baseline), discharge, and follow-up to six months

(10). Thus, utilizing data from the ESCAPE trial (10) the objective of this analysis was to: i) explore the

longitudinal changes of LFTs in patients treated for ADHF, ii) explore the effects of hemodynamic profile on

various LFTs, iii) explore the prognostic implications of MELD scoring on a broad HF population.

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Methods

Study Population

This study is a retrospective analysis of the publically available and de-identified limited access dataset from

the ESCAPE trial provided by the National Heart, Lung, and Blood Institute (NHLBI). According to NHLBI policy,

datasets from major clinical trials funded by NHLBI include the protocol and all collected variables with their

descriptions and definitions. Documentation for limited access datasets is comprehensive and sufficiently

clear to enable investigators who are not familiar with a specific dataset to use it.

The original study was a multicenter trial that compared therapy guided by pulmonary artery catheters

with therapy guided by clinical assessment in hospitalized patients with acute decompensated HF (10).

Patients were admitted for New York Heart Association (NYHA) class IV symptoms, had at least one prior

admission for exacerbation of HF within six months before randomization, and had left ventricular ejection

fraction (LVEF) < 30% by contrast ventriculography, radionuclide ventriculography, or quantitative

echocardiography within one year before randomization. For this paper, we analyzed the subset of patients

that had both total bilirubin and creatinine available at baseline (N = 346). However, not all patients had

complete LFT data for every time point.

Liver function tests

Liver function tests were recorded in both arms at admission, discharge, and follow-up of two weeks, one

month, two months, three months, and six months. For our analysis, patients without recorded baseline

creatinine or total bilirubin were excluded. The prevalence of patients with abnormal total bilirubin (Tbili),

aspartate transaminase (AST), alanine transaminase (ALT), albumin, and creatinine (Cr) were calculated from

admission with ADHF through the six-month follow up. The cut-offs for abnormal values were Tbili > 1.0

mg/dL, AST > 40 IU/L, ALT > 40 IU/L, serum albumin < 3.4 g/dL, and Cr > 1.3mg/dL.

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For patients randomized to the Swan-Ganz guided therapy arm, the following hemodynamic variables

were recorded and calculated: central venous pressure (CVP), pulmonary artery systolic, diastolic and mean

pressure, pulmonary capillary wedge pressure, systemic vascular resistance, mixed venous oxygen saturation,

arterial blood pressure, and cardiac index (CI). In this study we utilized CVP and CI values recorded at the time

of admission (decompensated heart failure). The Student’s t-test was utilized to determine if there are

significant differences in mean hemodynamic profiles (CVP and CI) by baseline LFT status (i.e., abnormal vs.

normal).

Statistical Analysis

The MELD-XI score was calculated using the following formula: (5.11* Ln total bilirubin) + (11.76 * Ln

creatinine) + 9.44]. Differences in baseline characteristics by MELD-XI score were compared using Pearson’s

chi-square for categorical variables, and Student’s t-test and Wilcoxon rank sum test for continuous variables.

A generalized estimating equation (GEE) was used to test for differences in LFT status (abnormal vs. normal)

from the baseline (admission) visit to the six-month visit. Student’s t-test was used to test for difference of

mean CVP and CI by LFT status (normal vs. abnormal). Kaplan-Meier survival curves and log-rank statistics

were utilized to assess admission (baseline) LFTs and MELD-XI score associated with a composite endpoint of

death, re-hospitalization, or heart transplant. Cox Proportional Hazard models were used to estimate risk of

the composite endpoint of death, re-hospitalization, or heart transplant for each of the baseline LFTs and

MELD-XI score. The LFTs were dichotomized by their respective abnormal cut-points as shown in Table 2 and

the MELD-XI was dichotomized at the median value. Baseline MELD-XI was categorized by the median value (<

11.4 vs. ≥ 11.4), tertiles (< 8.7 vs. ≥ 8.7 to < 13.9, vs. ≥ 13.9), quartiles (< 6.8 vs. ≥ 6.8 to < 11.4 vs. ≥ 11.4 to <

15.5 vs. ≥ 15.5),), and by using a classification and regression tree (CART) approach (< 16.8 vs. ≥ 16.8). CART is

a nonparametric data-mining tool that can segment data into meaningful subgroups and has been adapted for

failure time data using the Martingale Residuals of a Cox model to approximate chi-square values for all

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possible cut-points (http://econpapers.repec.org/software/bocbocode/s456776.htm). We applied the CART

approach to identify a potential novel cut-point that is not based on the distribution (i.e., median, tertiles, and

quartiles) of the MELD-XI score. All statistics was statistical analyses was performed using Stata/MP 12.1

(StataCorp LP, College Station, TX).

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Results

Study Population

Among the 346 patients admitted with ADHF that had both total bilirubin and creatinine available at baseline,

75% were male, 59% were white, 47% had an ischemic cardiomyopathy and 31% has diabetes at baseline

(Table 1). When MELD score was dichotomized at the median value (11.4), we found statistically significant

differences for the baseline characteristics between high and low MELD-XI. Specifically, individuals with high

MELD (≥ 11.4) were older, and more likely to be male and to have an ischemic cardiomyopathy. Additionally,

total bilirubin, direct bilirubin, and creatinine were all significantly higher among invidious with high MELD

score.

Longitudinal trends of LFTs

Overall, 312 patients (90%) had at least one abnormal LFT at baseline. The prevalence of individuals with an

abnormal LFT significantly decreased from baseline to six months for AST, ALT, albumin, total bilirubin, and

direct bilirubin, while there was no significant difference in the prevalence of abnormal creatinine (Table 2 and

Figure 1). LFTs appeared to be more labile than creatinine (Figure 1) from the decompensated state to stable

condition. The percentage of patients with elevated total bilirubin decreased from 36% on admission for ADHF

to 17% on a six-month follow-up, and percent of those with decreased albumin changed from 30% to 10% in

the same time frame, creatinine remained elevated in about half of the patients. In the end of the follow-up,

LFTs remained persistently elevated in 11 to 16% of patients while creatinine was increased in 45%, not

significantly different from the baseline (51.5%). The cohort was divided into patients that had morbidity or

mortality (cardiac re-hospitalization/transplant or death, respectively) in the follow up period, and the

prevalence of abnormal LFTs and creatinine was trended (data not included). In those patients that were re-

hospitalized or underwent transplant a similar trend was seen to that shown in figure 1. Whereas patients

that died in the follow up period did not show a significant trend.

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Hemodynamic profiles of cardiac hepatopathy

The hemodynamic profiles of patients randomized to the pulmonary arterial catheter arm with available LFTs

and Creatinine were analyzed to determine if there are significant differences in mean admission CVP and CI

comparing patients with abnormal vs. normal Creatinine, total bilirubin, albumin, AST and ALT (Table 3). CVP

was used as a surrogate for congestion, while CI reflected the output state. In patients with abnormal total

bilirubin, we found a significantly lower CI (1.8 vs. 2.1; P < 0.001) and higher CVP (14.2 vs. 12.0; P = 0.03) when

compared to patients with normal total bilirubin. Patients with elevated creatinine did not show significant

differences in mean CI or CVP when compared to patients with normal creatinine. Patients with elevated AST

had significantly higher CVP (15.4 vs. 12.2; P = 0.01) and a trend towards lower CI (Table 3). The levels of

albumin did not seem to be related to either hemodynamic profile.

Association of MELD-XI score and LFTs with a composite endpoint of death, cardiac re-hospitalization, and

heart transplant

Of the 346 patients in this analysis of the ESCAPE cohort, 55.8% (N = 193) died, were re-hospitalized, or

underwent heart transplant in the six month follow-up period. When MELD-XI was categorized by percentile

cut-points (median, tertiles, and quartiles), the Kaplan-Meier survival curves (Figures 2A to 2C) revealed that

patients in the highest percentile categories (i.e., ≥ median, third tertile, and fourth quartile, respectively)

were associated with borderline significant poorer outcomes. When a CART approach was used to identify a

potential novel cut-point, we found that patients with a MELD-XI score ≥ 16.8 (observed in 18% of patients)

had a significantly poorer outcomes compared to patients with a MELD-XI < 16.8 (Figure 2D, P < 0.001). The 6-

month event-free survival was 23.5% for patients in the high MELD-XI score group (≥ 16.8) compared to 46.2%

for patient in the low MELD-XI score group (< 16.8). Because the MELD-XI score is comprised of total bilirubin

and creatinine, we also assessed whether they were associated with the composite end point. We found that

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patients with abnormal creatinine (> 1.3) had a significantly increased risk of the composite endpoint (Figure

3A, P < 0.01) and there was no difference in outcomes for patients with abnormal (> 1.0) vs. normal total

bilirubin (Figure 3B). CART analyses did not yield a novel cut-point for any of the LFTs.

Cox proportional hazard models

The MELD-XI score and LFTs were analyzed in univariable Cox proportional hazard models to estimate the

magnitude of risk for the association with the composite endpoint (Table 4). Each LFT was analyzed as

dichotomous variable determined by the established clinical cut-points (same cut-points listed in Table 2) and

as continuous variables. The natural log (Ln) of total bilirubin and creatinine were also analyzed at the median

cut-point and as a continuous variable. ALT, AST, Albumin, total bilirubin, and direct bilirubin were not

associated with the composite endpoint. However, creatinine and MELD-XI were associated with increased

risk of the composite endpoint in the univariable analyses. When the main effects for each LFT and the MELD-

XI score were analyzed in separate multivariable models, creatinine and MELD-XI were still associated with

increased risk of the composite endpoint. However, when all the LFTs and the MELD-XI score dichotomized at

the CART cut-point were analyzed in a single model, adjusting for age, gender, race, BMI, diabetes, and SBP,

elevated MELD-XI score was associated with a 2-fold (HR = 2.06; 95% CI 1.05 – 4.03) increased risk of the

composite endpoint. None of the hazard ratios for the LFTs were statistically significant in the final model.

We also explored a final model using the original distributions of total bilirubin and creatinine, and the results

were consistent (data not shown).

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Discussion

In this post hoc analysis of the limited access dataset from the ESCAPE trial, we analyzed longitudinal trends of

LFTs and creatinine in patients treated for ADHF and found that LFTs are a more dynamic marker of a

decompensated state. While the proportion of patients with abnormal LFTs decreased two-and three-fold

from admission to the hospital with ADHF to a six month follow-up, creatinine remained elevated in about half

of the patients. In terms of absolute values, creatinine did not significantly change through the duration of the

study, while LFTs improved substantially, especially among patients who had abnormal LFTs at baseline.

We also found that both congestion and low output contributed to LFT abnormalities, particularly, total

bilirubin and AST. Albumin and, surprisingly, creatinine, did not differ between normal or elevated CVP

(surrogate of congestion) or normal and decreased CI (low output state). Finally, we found that elevated

MELD-XI score was associated with poor patient outcomes in this population of patients with ADHF even after

adjusting for baseline LFTs and patient characteristics.

High prevalence of abnormal LFTs in HF have been reported previously, although the results in our

analyses indicate a higher prevalence than in prior studies. Patients included in the ESCAPE cohort required an

EF < 30%, prior recent admissions for ADHF, and at least three months of symptoms. In the analysis of the

EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) and SURVIVE

(The Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trials (3, 4)

patients with low SBP were excluded, these patients were included in the ESCAPE cohort, also the population

was sufficiently ill to make use of the pulmonary artery catheters reasonable. The inclusion of a greater

severity of HF in the ESCAPE trial likely explains why 90% of our patients had at least one abnormal LFT at

admission compared to near 50% in other cohorts.

The CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) trial

studied a mixed preserved and reduced LVEF population with chronic HF and found abnormal alanine

aminotransferase was present in 3.1% of patients, low albumin in 18.3%, and total bilirubin in 13.0% of

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patients (1). The results from the CHARM trial are similar to the six month follow-up values in our analysis, but

far lower than our baseline data on admissions for ADHF. Even their cohort of patients with reduced LVEF had

lower representation of abnormal LFTs than our cohort. In the EVEREST (Efficacy of Vasopressin Antagonism in

Heart Failure Outcome Study with Tolvaptan) analysis, the prevalence of LFT abnormalities was high at

baseline and remained virtually unchanged during hospitalization, with the exception of elevated total

bilirubin, but still the prevalence of abnormal LFTs they observed (ALB 17%, AST 21%, ALT 21%, and total

bilirubin 26%) was somewhat lower than ours (29%, 24%, 24%, and 36%, respectively)(4). However, in our

analysis, all LFTs showed significant post discharge improvement. Unlike in other studies, we could track the

LFTs of the ESCAPE patients until 6 months of follow-up, while the EVEREST patients were only followed for

eight weeks (4). Hence, we were able to report more detailed analysis of longitudinal changes of LFTs in HF

than previously published studies. We were also able to compare LFT trends with the respective changes in

creatinine and found that LFT mirrored more closely the pattern that is seen in B-type natriuretic peptide

(BNP) levels after treatment of ADHF. Conversely, the prevalence of creatinine abnormalities remained near

50% at all time points. We see that LFTs are more labile than creatinine from the decompensated state to

stable treated HF.

To evaluate which biomarker is associated with a congestive versus ischemic state we utilized patients

of the ESCAPE trial in the pulmonary artery catheter arm. We found that patients with elevated total bilirubin

had significantly lower CI and higher CVP. This result is similar to prior studies that evaluated a similar patient

population monitored with Swan-Ganz catheters (11, 12) but varies from other studies that found total

bilirubin to only be associated with an elevated central venous pressure and tricuspid regurgitation (13, 14).

We saw a similar trend with AST; patients with elevated AST had lower mean CI and significantly higher CVP.

In the CHARM trial cohort, the total bilirubin elevation was observed in patients with physical signs of

congestion, but invasive hemodynamics was not available(1). Van Deursen et al. showed that total bilirubin

levels, as well as AST and ALT, were associated with both low CI and elevated CVP(14). Interestingly, patients

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with abnormally low albumin did not, by our findings, have a significant difference in mean CI and CVP

suggesting albumin is less influenced by the hemodynamic state. Further prospective study is needed to

better evaluate the relationship between abnormal LFTs and hemodynamic compromise in ADHF. However, it

is clinically useful to understand the LFT profile one may expect in patients presenting with ADHF with varied

forms of hemodynamic compromise.

We also found that creatinine did not appear to be related to either elevated CVP or low CI. In the prior

studies, creatinine was shown to be higher in congested state (high CVP) (15, 16). However, in the Cleveland

Clinic series, the worsening of renal function (change in creatinine), rather than creatinine per se, was the

focus of the study. In the current paper, we did not target the change in creatinine, and therefore our data are

not directly comparable. As for the second study (15), the population was completely different from the

ESCAPE and included all comers to the catheterization laboratory for a Swan-Ganz catheter, with a significant

share of patients with better LVEF and generally less sick than patients included into the present analysis.

Because HF is a multi-system disease, application of the MELD-XI score, which combines parameters of

both hepatic and renal function for prognostic and risk-stratification purposes, is appealing. To our knowledge,

it has never been assessed in the broad HF population admitted for acute decompensation and followed for

substantial length of time. Previous studies have analyzed this score in different subsets of HF populations. In

patients undergoing heart transplantation, individuals with a higher pre-transplantation MELD or modified

MELD score (with albumin included instead of INR) had worse outcomes 30 days post-transplant and reduced

long-term survival over a 10-year follow-up (8). When the MELD-XI score was categorized by percentiles

(Figures 2A to 2C), we consistently found that high MELD-XI was associated with poor patient outcomes;

however, none of the log-rank P-values were statistically significant. Thus, using CART analyses we found a

novel cut-point which revealed that patients with a MELD-XI score ≥ 16.8 had significantly poorer patient

outcomes compared to patients with a MELD-XI score < 16.8 (Figure 2D). When all baseline LFTs, patient

characteristics, and MELD-XI score were included in a single multivariable model (Table 4), we found that high

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MELD-XI score was significantly associated with poor patient outcomes and none of the LFTs were statistically

significant. Thus, our results suggest that MELD-XI score, which includes the Ln of total bilirubin and

creatinine, is an independent predictor of patient outcomes. In a separate study of ambulatory patients with

HF awaiting heart transplant, MELD, MELD-XI, and MELD NA (including serum sodium) scores all predicted

poor outcomes, poor outcomes defined as death/transplantation/ventricular assist device requirement. In

that study, authors also found that MELD scores were related to congestion but not to low output. The MELD

scores were stronger predictors of adverse outcomes than their individual components(6). Of note, while total

bilirubin by itself was a predictor of poor outcomes, creatinine was not, opposite to our findings. In HF

patients undergoing ventricular assist device implantation, lower MELD or MELD-XI scores were associated

with better overall survival with a higher predictive power for MELD-XI (9). By their multivariable analysis, high

creatinine levels by themselves did not predict poor outcomes, meaning that bilirubin was a major contributor

to prognostic significance of the score. Some other data investigated the predictive role of LFTs in regards to

prognosis in HF. In chronic stable HF patients of the CHARM trial, total bilirubin predicted poor outcomes

stronger than creatinine (1). Total bilirubin and albumin predicted poor outcome in the EVEREST trial; no

comparison with creatinine was made (4, 12). In our analyses of advanced HF, high MELD-IX scores were

associated with poor outcomes at six months. When the MELD-XI scores were dichotomized at a novel cut-

point determined by CART analyses, patients with MELD-XI score ≥ 16.8 (observed in 18% of patients) had

increased risk of death, re-hospitalization, or transplant at the six months (Figure 2D). This is similar, although

slightly higher, than the average optimal cutoff value derived from 1-year ROC analyses of MELD scores in a

recent study of outpatients with severe heart failure undergoing transplant workup(6). Creatinine was

independently associated with poor outcomes (Figure 3A); however, in the final model, which adjusts for all

LFT’s and patient demographics, MELD-XI was the only factor significantly associated with the composite

endpoint. Worse outcomes are seen in patients with a greater degree of multi-system dysfunction and, as

expected, there appears to be added prognostic value when combining creatinine and bilirubin in this manner.

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Limitations

We acknowledge potential limitations of this analysis. Firstly, this was a post hoc analysis of data collected in

the context of a clinical trial with specific inclusion and exclusion criteria, which could limit the generalizability

of these findings. The sample size of patients with abnormal LFTs and Creatinine within the pulmonary artery

catheter arm of the data set was relatively small, limiting the power of our hemodynamic results. Additionally,

LFT data was not available for all patients at every time point of follow-up

Conclusions

Abnormalities in liver function tests are exceedingly common among acutely decompensated heart failure

patients, and therefore, further support the concept of heart failure as a multisystem disease. Our data

suggested the prevalence of abnormal LFTs showed a significant decline in the post-discharge period of

treated HF patients and is perhaps a better surrogate of systemic congestion than creatinine. Although

additional prospective studies are needed, multi-organ system composite scoring methods like MELD-XI may

have important prognostic implications when applied to the general heart failure population.

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Acknowledgments

The ESCAPE is conducted and supported by the NHLBI in collaboration with the ESCAPE Study

Investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does

not necessarily reflect the opinions or views of the ESCAPE or the NHLBI.

Disclosures

None.

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11. Biegus J, Zymlinski R, Sokolski M, Nawrocka S, Siwolowski P, Szachniewicz J, et al. Liver function tests in

patients with acute heart failure. Polskie Archiwum Medycyny Wewnetrznej. 2012;122(10):471-9.

12. Shinagawa H, Inomata T, Koitabashi T, Nakano H, Takeuchi I, Naruke T, et al. Prognostic significance of

increased serum bilirubin levels coincident with cardiac decompensation in chronic heart failure. Circulation

journal : official journal of the Japanese Circulation Society. 2008;72(3):364-9.

13. Lau GT, Tan HC, Kritharides L. Type of liver dysfunction in heart failure and its relation to the severity of

tricuspid regurgitation. The American journal of cardiology. 2002;90(12):1405-9.

14. van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA. Abnormal liver

function in relation to hemodynamic profile in heart failure patients. Journal of cardiac failure. 2010;16(1):84-

90.

15. Guglin M, Rivero A, Matar F, Garcia M. Renal dysfunction in heart failure is due to congestion but not

low output. Clinical cardiology. 2011;34(2):113-6.

16. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, et al. Importance of venous

congestion for worsening of renal function in advanced decompensated heart failure. Journal of the American

College of Cardiology. 2009;53(7):589-96.

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Table 1. Baseline characteristics of the study population: overall and dichotomized by MELD-XI score

Overall MELD-XI Score2

Characteristic

Included1

Excluded P-value3

High (≥ 11.4) Low (< 11.4)

P-value4

N = 346 N = 87 (N = 176) (N = 170)

Age, mean (SD) 55.5 (13.8) 58.7 (14.2) 0.055 59.1 (13.9) 51.7 (12.7) < 0.001

Gender, N (%)

Men 259 (74.9) 62 (71.3) 150 (85.2) 109 (64.1)

Women 87 (25.1) 25 (28.7) 0.497 26 (14.8) 61 (35.9) < 0.001

Race, N (%)

White 205 (59.3) 53 (60.9) 113 (64.2) 92 (54.1)

Non-white 141 (40.8) 34 (39.1) 0.776 63 (35.8) 78 (45.9) 0.056

BMI, mean (SD) 28.8 (6.6) 29.7 (7.4) 0.300 28.3 (6.1) 29.4 (7.1) 0.122

Idiopathic etiology, N (%)

Yes 124 (35.9) 26 (30.2) 57 (32.6) 67 (39.4)

No 221 (64.1) 60 (69.8) 0.320 118 (67.4) 103 (60.6) 0.186

Ischemic etiology, N (%)

Yes 164 (47.5) 49 (57.0) 96 (54.9) 68 (40.0)

No 181 (52.5) 37 (43.0) 0.117 79 (45.1) 102 (60.0) 0.006

Diabetes at baseline, N (%)

Yes 107 (31.0) 33 (38.4) 57 (32.6) 50 (29.4)

No 238 (69.0) 53 (61.6) 0.192 118 (67.4) 120 (70.6) 0.526

Liver Function Tests, median (25th

to 75TH

)

ALT 27.0 (19.0 – 39.0) 23.5 (22 – 32.0) 0.496 27.0 (18.0 – 35.5) 27.0 (20.0 – 43.0) 0.239

AST 29.0 (22.0 – 39.5) 37.0 (31.0 – 37.0) 0.193 29.0 (22.0 – 39.0) 29.0 (22.0 – 40.0) 0.706

Albumin (Alb) 3.6 (3.3 – 4.0) 3.45 (3.3 – 3.7) 0.401 3.6 (3.2 – 4.0) 3.6 (3.3 – 4.0) 0.785

Total bilirubin (TBili) 0.8 (0.4 – 1.2) N/A -- 1.1 (0.8 –1.5) 0.5 (0.2 – 0.8) < 0.001

Direct bilirubin (DBili) 0.1 (0.1 – 0.6) 0.35 (0.09 – 0.6) 0.871 0.3 (0.2 – 0.6) 0.2 (0.09 – 0.6) 0.020

Creatinine (Cr) 1.4 (1.1 – 1.8) 1.4 (1.1 – 1.9) 0.448 1.7 (1.4 – 2.1) 1.1 (0.9 – 1.3) < 0.001

Peak Vo2, mean (SD) 9.9 (3.1) 11.3 (1.3) 0.134 9.96 (3.07) 9.78 (3.20) 0.752

6-min walk, mean (SD) 420.8 (421.4) 386 (44.8) 0.517 453.1 (424.5) 387.6 (416.9) 0.169

Bold p-values indicate a statistically significant difference between high MELD and low MELD

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1Among patients who have both total bilirubin at baseline and creatinine at baseline (N = 346); patients that were excluded did not have both total bilirubin

at baseline and creatinine at baseline 2 MELD Score is dichotomized at the median value

3 To test for differences between patients that were included and excluded, P-values were calculated using Pearson’s chi-square for categorical variables,

Student’s t-test comparing mean variables, and Wilcoxon rank sum test comparing median values.

4 To test for differences between high MELD and low MELD, P-values were calculated using Pearson’s chi-square for categorical variables, Student’s t-test

comparing mean variables, and Wilcoxon rank sum test comparing median values.

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Table 2. Prevalence of abnormal LFTs for each time-point among individuals with total bilirubin at baseline and baseline creatinine

Baseline Discharge 2 weeks 1 month 2 months 3 months 6 months P-value1

ALT Normal N 250 132 126 139 112 133 97

Normal % 75.7 80.0 73.3 76.8 76.7 82.1 82.9

Elevated (> 40), N 80 33 46 42 34 29 20

Elevated (> 40), % 24.2 20.0 26.7 23.2 23.3 17.9 17.1 < 0.001

Median ALT 59.5 40 43 30 32 29.5 29

AST Normal N 257 128 134 157 122 133 101

Normal % 76.5 77.1 76.1 85.8 83.6 81.1 86.3

Elevated (> 40), N 79 38 42 26 24 31 16

Elevated (> 40), % 23.5 22.9 23.9 14.2 16.4 18.9 13.7 0.009

Median AST 56 35.5 58 30 29.5 26 27

Albumin Normal N 225 116 145 154 124 142 103

Normal % 70.7 71.2 86.8 86.0 86.1 88.2 89.6

Decreased (< 3.4), N 93 47 22 25 20 19 12

Decreased (< 3.4), % 29.3 28.8 13.2 14.0 13.9 11.8 10.4 < 0.001

Median Alb 3.1 3.3 3.6 3.7 3.6 3.7 3.7

Total bilirubin Normal N 221 119 122 130 119 130 98

Normal % 63.9 68.4 68.2 70.7 81.5 79.7 83.1

Elevated (> 1.0), N (%) 125 55 57 54 27 33 20

Elevated (> 1.0), % 36.1 31.6 31.8 29.4 18.5 20.3 16.9 < 0.001

Median TBili 1.4 1 0.9 0.9 0.7 0.7 0.7

Direct bilirubin Normal. N 131 85 91 89 78 97 69

Normal. % 60.1 63.4 73.4 76.7 75.7 84.4 84.2

Elevated (> 0.3), N 87 49 33 27 25 18 13

Elevated (> 0.3). % 39.9 36.6 26.6 23.4 24.4 15.6 15.8 < 0.001

Median Dir Bili 0.6 0.4 0.3 0.3 0.2 0.2 0.2

Creatinine Normal. N 168 173 114 123 94 92 74

Normal. % 48.5 53.2 46.9 49.8 46.1 42.8 55.2

Elevated (> 1.3), N 178 152 129 124 110 123 60

Elevated (> 1.3), % 51.5 46.8 53.1 50.2 53.9 57.2 44.8 0.055

Median Cr 1.8 1.8 1.9 1.9 1.8 1.7 1.8

Bold P-values indicate a statistically significant difference in percentage of patients with abnormal LFTs from baseline to 6 months

1 P-values were generated from a generalized estimating equation (GEE)

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Table 3. CVP and CI by baseline LFT and creatinine status

LFT Status at baseline1

CVP, mean (SD) CI, mean (SD)

AST abnormal (> 40) 15.4 (9.1) 1.9 (0.65)

AST normal (≤ 40) 12.2 (6.6) 2.0 (0.64)

P-value

0.010 0.482

ALT abnormal (> 40) 14.3 (6.4) 2.0 (0.62)

ALT normal (≤ 40) 12.4 (9.7) 2.0 (0.63)

P-value 0.139 0.941

Albumin abnormal (< 3.4) 13.1 (6.9) 1.9 (0.64)

Albumin normal (≥ 3.4) 12.7 (6.9) 2.0 (0.58)

P-value 0.693 0.629

Total bilirubin abnormal (> 1.0) 14.4 (6.5) 1.8 (0.48)

Total bilirubin li normal (≤ 1.0) 12.0 (6.8) 2.1 (0.69)

P-value 0.030 < 0.001

Direct bilirubin abnormal (≥ 0.3) 15.5 (6.7) 1.8 (0.56)

Direct bilirubin li normal (< 0.3) 9.9 (5.7) 2.1 (0.58)

P-value < 0.001 0.006

Creatinine abnormal (> 1.3) 13.8 (6.6) 2.0 (0.69)

Creatinine normal (≤ 1.3) 11.8 (6.8) 2.0 (0.56)

P-value 0.054 0.972

Bold P-values indicate a statistically significant difference

1P-values were calculated from Student’s t-test comparing mean CVP by baseline LFT Status and mean

CI by baseline LFT Status

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Table 4. Cox proportional hazard models for the LFTs and MELD-XI score

Variable1

Univariable HR (95% CI)

Main effects models

Adjusted HR (95% CI)2

Final Model

Adjusted HR (95% CI)3

ALT, abnormal cut-point 1.06 (0.76 – 1.49) 1.12 (0.79 – 1.58)4

1.25 (0.73 – 2.12)

ALT, continuous 1.00 (0.99 – 1.00) 1.00 (0.99 – 1.00)4

--

AST, abnormal cut-point 1.19 (0.80 – 1.56) 1.06 (0.75 – 1.50)4

0.91 (0.53 – 1.59)

AST, continuous 1.00 (0.99 – 1.00) 1.00 (0.99 – 1.00)4

--

Albumin, abnormal cut-point 0.76 (0.54 – 1.07) 0.74 (0.52 – 1.05)4

0.79 (0.50 – 1.24)

Albumin, continuous 1.09 (0.86 – 1.37) 1.05 (0.83 – 1.35)4

--

Total bilirubin, abnormal cut-point 1.01 (0.75 – 1.35) 0.95 (0.70 – 1.29)4

--

Total bilirubin, continuous 0.92 (0.70 – 1.21) 0.92 (0.69 – 1.22)4 --

Ln total bilirubin, median 0.99 (0.75 – 1.32) 0.90 (0.67 – 1.22)4 0.74 (0.45 – 1.23)

Ln total bilirubin, continuous 0.89 (0.75 – 1.07) 0.90 (0.75 – 1.07)4 --

Direct bilirubin, abnormal cut-point 1.09 (0.76 – 1.57) 1.02 (0.69 – 1.51)4

0.98 (0.62 – 1.55)

Direct bilirubin, continuous 1.05 (0.65 – 1.71) 0.93 (0.54 – 1.61)4

--

Creatinine, abnormal cut-point 1.49 (1.12 – 1.98) 1.36 (1.00 – 1.87)5 --

Creatinine, continuous 1.50 (0.20 – 1.87) 1.36 (1.07 – 1.74)5

--

Ln creatinine, median

1.49 (1.12 – 1.98) 1.36 (1.00 – 1.87)5

1.21 (0.73 – 2.00)

Ln creatinine, continuous 2.00 (1.38 – 2.89) 1.77 (1.17 – 2.65)5

--

MELD-XI, median 1.27 (0.96 – 1.69) 1.43 (1.00 – 2.07)5

--

MELD-XI, continuous 1.02 (1.00 – 1.05) 1.05 (1.01 – 1.09)5

--

MELD-XI, CART cut-point6

1.84 (1.32 – 2.57) 1.94 (1.31 – 2.89)5

2.06 (1.05 – 4.03)

Bold values indicate a statistically significant hazard ratio

Abbreviations: Ln, natural log; HR, hazard ratio; CI, confidence interval 1The LFTs and MELD-XI scores were analyzed as dichotomous variables (clinical cut-point or median cut-point) and as continuous

variables. The abnormal cut-points are provided in Table 2. 2For the main effects models, each LFT and MELD-XI variable was analyzed in a separate adjusted model.

3A final model was created that included ALT, AST, albumin, total bilirubin, direct bilirubin, creatinine, MELD-XI, age, gender, race, BMI,

diabetes, and SBP. 4Adjusted for age, gender, race, BMI, diabetes, SBP, and creatinine

5Adjusted for age, gender, race, BMI, diabetes, SBP, and total bilirubin

6A novel cut-point was determined using a classification and regression tree (CART) approach.

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Figure Legends

Figure 1. Prevalence of abnormal LFTs from admission to six-month follow-up. The cut-offs for abnormal

values were serum creatinine (Cr > 1.3mg/dL), total bilirubin (TBili > 1.0mg/dL), aspartate

transaminase (AST > 40 IU/L), alanine transaminase (ALT > 40 IU/L), and albumin (ALB < 3.4

g/dL).

Figure 2. Kaplan-Meier survival curves for the composite endpoint (death, cardiac re-hospitalization, and

Heart transplant (Htx) by MELD-XI score. (A) MELD-XI score dichotomized at the median, (B)

MELD-XI score categorized by tertiles, (C) MELD-XI score categorized by quartiles, and (D)

MELD-XI score dichotomized at a cut-point determined by CART analysis. P-values are from the

log-rank test.

Figure 3. Kaplan-Meier survival curves for composite endpoint (death, cardiac re-hospitalization, and

Heart transplant (Htx) by (A) baseline creatinine (abnormal [>1.3] vs. normal [≤ 1.3]), and (B)

baseline total bilirubin (abnormal [> 1.0] vs normal [≤ 1.0]). P-values are from the log-rank test.

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Admission Discharge 2 weeks 1 month 2 month 3 month 6 monthCr 51.5 46.8 53.1 50.2 53.9 57.2 44.8Tbili 36.1 31.6 31.8 29.4 18.5 20.3 16.9Dbili 39.9 36.6 26.6 23.4 24.4 15.6 15.8AST 23.5 22.9 23.9 14.2 16.4 18.9 13.7ALT 24.2 20 26.7 23.2 23.3 17.9 17.1Alb 29.3 28.8 13.2 14 13.9 11.8 10.4

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Longitudinal Trends, Hemodynamic Profiles, and Prognostic Value of Abnormal

Liver Function Tests in Patients with Acute Decompensated Heart Failure: an

Analysis of the ESCAPE Trial

Highlights:

• We analyzed LFT abnormalities in severely decompensated heart failure patients.

• Patients admitted with heart failure have a high prevalence of abnormal LFTs.

• Abnormal LFTs are a dynamic marker of an impaired hemodynamic state.

• Elevated total bilirubin was associated with a lower cardiac index and higher CVP.

• Patients with elevated MELD-XI scores had a 2-fold increased risk of poor outcomes.