Relation of Serum Uric Acid Levels and Outcomes Among

Patients Hospitalized for Worsening Heart Failure With

Reduced Ejection Fraction (from the Efcacy of Vasopressin
Antagonism in Heart Failure Outcome Study With Tolvaptan Trial)
Muthiah Vaduganathan, MD, MPHa,*, Stephen J. Greene, MDb, Andrew P. Ambrosy, MDc,
Robert J. Mentz, MDd, Haris P. Subacius, MAe, Ovidiu Chioncel, MDf, Aldo P. Maggioni, MDg,
Karl Swedberg, MDh, Faiez Zannad, MDi, Marvin A. Konstam, MDj, Michele Senni, MDk,
Michael M. Givertz, MDl, Javed Butler, MD, MPHm, and Mihai Gheorghiade, MDb, on behalf of the
EVEREST trial investigators
We investigated the clinical proles associated with serum uric acid (sUA) levels in a large
cohort of patients hospitalized for worsening chronic heart failure with ejection fraction
(EF) 40%, with specic focus on gender, race, and renal function based interactions. In
3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes
were compared across sUA quartiles. The primary end points were all-cause mortality and
a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was
9.9 months. Mean sUA was 9.1 2.8 mg/dl and was higher in men than in women (9.3 2.7
vs 8.7 3.0 mg/dl, p <0.001) and in blacks than in whites (10.0 2.7 vs 9.0 2.8 mg/dl, p
<0.001). Higher sUA was associated with lower systolic blood pressure and EF, higher
natriuretic peptides, and more impaired renal function. After accounting for 24 baseline
covariates, in patients with enrollment estimated glomerular ltration rate 30 ml/min/
1.73 m2, sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44,
95% condence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio
1.44, 95% condence interval 1.26 to 1.64, p <0.001). However, in patients with estimated
glomerular ltration rate <30 ml/min/1.73 m2, sUA was not related with either end point
(both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use
were not signicant. In conclusion, sUA is commonly elevated in patients hospitalized for
worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and
pathophysiologic signicance of sUA among those with and without signicant renal
dysfunction. 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;-:-e-)
Hospitalization for worsening chronic heart failure
(WCHF) is a unique entity, distinguished by acute perturbations in clinical, neurohormonal, and laboratory indexes.1
Serum uric acid (sUA) levels have been shown to uctuate
with WCHF hospitalizations in large, prospectivelyfollowed ambulatory patients with heart failure (HF).2
Consistently, studies have suggested that sUA is a marker
of adverse prognosis in the setting of WCHF.3e11 sUA may

be strongly inuenced by impaired renal function,12 race,13

gender,14 and diuretic therapy. The Efcacy of Vasopressin
Antagonism in Heart Failure Outcome Study with Tolvaptan
(EVEREST)15e17 trial database provides detailed, longitudinal, patient-level data on sUA and other clinical parameters during and after hospitalization for WCHF. Thus, we
aimed to evaluate the independent association between sUA
at the time of enrollment and clinical characteristics and

a
Department of Medicine, Massachusetts General Hospital, Boston,
Massachusetts; bCenter for Cardiovascular Innovation, Northwestern
University Feinberg School of Medicine, Chicago, Illinois; cDepartment of
Medicine, Stanford University School of Medicine, Stanford, California;
d
Duke University Medical Center, Durham, North Carolina; eDivision of
Cardiology, Department of Medicine, Northwestern University Feinberg
School of Medicine, Chicago, Illinois; fInstitute of Emergency for
Cardiovascular Diseases Prof. C.C. Iliescu, Cardiology, Bucharest,
Romania; gResearch Center of the Italian Association of Hospital Cardiologists (ANMCO), Florence, Italy; hUniversity of Gothenburg, Gothenburg, Sweden; iDepartment of Cardiology, Nancy University, Nancy,
France; jTufts Medical Center, Boston, Massachusetts; kDipartimento

Cardiovascolare, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo,

Italy; lCardiovascular Division, Brigham and Womens Hospital, Harvard
Medical School, Boston, Massachusetts; and mDivision of Cardiology,
Emory University School of Medicine, Atlanta, Georgia. Manuscript
received July 21, 2014; revised manuscript received and accepted
September 2, 2014.
Otsuka Inc. (Rockville, Maryland) provided nancial and material
support for the EVEREST trial. Database management was performed by
the sponsor.
See page 8 for disclosure information.
*Corresponding author: Tel: (832) 725-7222; fax: (617) 726-6861.
E-mail address: muthu@md.northwestern.edu (M. Vaduganathan).

0002-9149/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjcard.2014.09.008

www.ajconline.org

The American Journal of Cardiology (www.ajconline.org)

Figure 1. Overall study design and analytical cohort selection. LVEF left ventricular ejection fraction; NYHA New York Heart Association.

Figure 2. Distribution and descriptive statistics of sUA levels. The primary predictor variable of baseline sUA was normally distributed with a mean and median
of approximately 9 mg/dl. The black curve represents the normal density distribution and the gray curve represents the kernel density distribution for this
sample. IQR interquartile range.

postdischarge outcomes in patients hospitalized for WCHF

with reduced ejection fraction (EF).
Methods
The study design16 and primary results15,17 of the
EVEREST trial have been previously described. In brief,
EVEREST was a global, multicenter, double-blinded, placebo-controlled randomized trial examining tolvaptan, an
oral vasopressin-2 receptor antagonist. Patients eligible for
enrollment were 18 years of age, hospitalized for WCHF

with New York Heart Association III-IV functional status,

EF 40% and presenting with 2 signs or symptoms of
volume overload. Relevant exclusion criteria include serum
creatinine >3.5 mg/dl; subjects currently treated with
hemoltration or dialysis; refractory, end-stage HF; or a life
expectancy <6 months. The ethics committee and institutional review board of each participating trial center
approved the study protocol. Patients were randomized to
receive oral tolvaptan 30 mg xed once daily or matching
placebo within 48 hours of hospital admission and was
continued for at least 60 days. Laboratory samples were

Heart Failure/Uric Acid and Hospitalized Heart Failure

Table 1
Baseline characteristics by serum uric acid quartile
Variable

Serum uric acid, (mg/dL), meanSD

Serum uric acid, (mg/dL), range
Tolvaptan assignment
Age (years), meanSD
Male
Race
Non-Hispanic White
Black
Asian
Hispanic
Other
Region
Eastern Europe
North America
South America
Western Europe
Weight (kg), meanSD
Systolic blood pressure (mmHg), meanSD
Diastolic blood pressure (mmHg), meanSD
Heart rate (bpm), meanSD
Jugular venous distension  10 cm
Rales
Peripheral edema*
Dyspnea
Ejection fraction (%),
meanSD
Blood urea nitrogen (mg/dL), median (IQR)
Creatinine (mg/dL),
median (IQR)
Estimated GFR (mL/min/1.73 m2), meanSD
Estimated GFR<30 (mL/min/1.73 m2)
Sodium (mEq/L),
median (IQR)
B-type natriuretic peptide (pg/ml), median (IQR)
N-terminal pro-B-type natriuretic peptide (pg/ml)
median (IQR)
Albumin (g/dL),
median (IQR)
QRS (ms), median (IQR)
Atrial brillation
Previous heart failure hospitalization
Ischemic heart failure etiology
NYHA class IV
Coronary artery disease
Previous myocardial infarction
Hypertension
Hypercholesterolemia
Diabetes
Chronic kidney disease
Peripheral vascular disease
Previous coronary bypass
Previous percutaneous coronary intervention
Automatic implantable cardioverter-debrillator
Chronic obstructive pulmonary disease
Baseline medication use
Allopurinol
Diuretics

Baseline Serum Uric Acid Quartiles

p-value

I
(n967)

II
(n1,012)

III
(n977)

5.81
1.2-7.0
514 (53.2%)
67.110.7
637 (65.9%)

80.5
7.1-8.8
494 (48.8%)
66.111.8
754 (74.5%)

9.80.6
8.9-10.8
464 (47.5%)
65.412
774 (79.2%)

12.91.8
10.9-21.0
504 (50.5%)
64.512.7
780 (78.1%)

869
42
1
40
16

876
63
1
59
14

836
73
2
47
21

816
107
5
45
31

(89.9%)
(4.3%)
(0.1%)
(4.1%)
(1.7%)

(86.6%)
(6.2%)
(0.1%)
(5.8%)
(1.4%)

(85.6%)
(7.5%)
(0.2%)
(4.8%)
(2.1%)

IV
(n999)

0.073
<0.001
<0.001
<0.001

(81.7%)
(10.7%)
(0.5%)
(4.5%)
(3.1%)
<0.001

494 (51.1%)
205 (21.2%)
144 (14.9%)
124 (12.8%)
79.818.2
124.920.5
74.312.5
78.814.8
196 (20.7%)
801 (83.7%)
778 (81.3%)
882 (92.3%)
29.67.8

452 (44.7%)
268 (26.5%)
172 (17%)
120 (11.9%)
8218.1
121.719.6
7312.4
79.215.5
248 (24.8%)
823 (82.1%)
789 (78.7%)
897 (89.5%)
28.27.8

379 (38.8%)
298 (30.5%)
171 (17.5%)
129 (13.2%)
8518.1
120.319.6
7312.9
80.316.4
291 (30.4%)
772 (79.9%)
767 (79.3%)
891 (92.2%)
27.18

245 (24.5%)
415 (41.5%)
189 (18.9%)
150 (15%)
86.220.4
115.217.9
70.412.7
80.715.7
308 (32.1%)
774 (79.8%)
783 (80.6%)
874 (90.4%)
25.48.2

<0.001
<0.001
<0.001
0.019
<0.001
0.083
0.450
0.078
<0.001

20 (17-27)
1 (0.9-1.3)

24 (19-31)
1.2 (1-1.4)

27 (21-35)
1.3 (1.1-1.6)

35 (26-48)
1.5 (1.3-1.9)

<0.001
<0.001

65.821.9
58 (6.1%)
140
(138-143)
481
(194-1137)
4070
(1650-8824)
3.8 (3.5-4.1)

60.320.1
53 (5.3%)
140
(138-142)
538.5
(254-1284)
3641
(1661-7468)
3.8 (3.4-4.1)

53.818.9
88 (9.2%)
140
(137-143)
746
(316-1474)
4256
(2241-8662)
3.8 (3.4-4.2)

44.417.4
223 (22.7%)
139
(136-142)
1106.5
(543-2126)
6800
(3642-12837)
3.7 (3.3-4)

<0.001
<0.001
<0.001

<0.001

121
258
740
659
323
689
485
693
450
379
137
205
159
141
125
73

121
277
783
653
371
725
518
717
491
387
216
223
207
174
127
98

123
311
786
641
401
687
506
693
473
363
280
191
209
181
152
100

125
288
810
614
468
685
492
705
499
401
421
209
253
205
173
124

<0.001
0.060
0.019
0.031
<0.001
0.423
0.678
0.958
0.549
0.563
<0.001
0.585
<0.001
0.006
0.007
0.004

(95-144)
(26.7%)
(76.7%)
(68.9%)
(33.4%)
(71.4%)
(50.2%)
(71.7%)
(46.9%)
(39.2%)
(14.2%)
(21.2%)
(16.4%)
(14.6%)
(12.9%)
(7.5%)

149 (15.4%)
931 (96.5%)

(97-150)
(27.4%)
(77.7%)
(65.4%)
(36.7%)
(71.6%)
(51.2%)
(70.8%)
(48.8%)
(38.2%)
(21.3%)
(22.1%)
(20.5%)
(17.2%)
(12.5%)
(9.7%)

110 (10.9%)
987 (97.7%)

(97-152)
(31.8%)
(80.9%)
(66.4%)
(41%)
(70.4%)
(51.8%)
(70.9%)
(48.6%)
(37.2%)
(28.7%)
(19.5%)
(21.4%)
(18.5%)
(15.6%)
(10.2%)

96 (9.8%)
951 (97.4%)

(100-155)
(28.8%)
(81.5%)
(62.5%)
(47%)
(68.6%)
(49.3%)
(70.6%)
(50.2%)
(40.1%)
(42.2%)
(21%)
(25.3%)
(20.5%)
(17.3%)
(12.4%)

85 (8.5%)
976 (98%)

<0.001
<0.001

<0.001
0.166
(continued)

The American Journal of Cardiology (www.ajconline.org)

Table 1
(continued)
Variable

Baseline Serum Uric Acid Quartiles

I
(n967)

ACEI/ ARB
Beta-Blockers
Mineralocorticoid receptor antagonists
Digoxin
Intravenous Inotropes
Statin

823
667
511
438
33
345

II
(n1,012)

(85.3%)
(69.1%)
(53%)
(45.4%)
(3.4%)
(35.8%)

880
725
573
496
32
368

p-value

III
(n977)

(87.1%)
(71.8%)
(56.7%)
(49.1%)
(3.2%)
(36.4%)

837
706
550
493
44
319

(85.8%)
(72.3%)
(56.4%)
(50.5%)
(4.5%)
(32.7%)

IV
(n999)
796
696
516
489
71
339

(79.9%)
(69.9%)
(51.8%)
(49.1%)
(7.1%)
(34%)

<0.001
0.346
0.065
0.132
<0.001
0.289

ACEI angiotensin converting enzyme inhibitor; ARB angiotensin II receptor blocker; GFR glomerular ltration rate; IQR interquartile range;
NYHA New York Heart Association; SD standard deviation.
* Peripheral edema was dened as slight/ moderate/ marked pedal or sacral edema.

Glomerular ltration rate estimated by Cockcroft-Gault formula.

Table 2
Causes of death and rehospitalization by baseline serum uric acid quartile
Baseline Serum Uric Acid Quartiles

Serum uric acid, (mg/dL), mean (SD)

Serum uric acid, (mg/dL), range
Primary Endpoints
All-cause mortality
CV mortality HF hospitalization
Secondary Endpoints
CV mortality
CV mortality CV hospitalization
Worsening HF *
HF mortality
HF hospitalization
MI mortality
MI hospitalization
Stroke mortality
Stroke hospitalization

p-value

I
(n967)

II
(n1,012)

III
(n977)

IV
(n999)

5.81
1.2-7.0

80.5
7.1-8.8

9.80.6
8.9-10.8

12.91.8
10.9-21.0

180 (18.6%)
293 (30.3%)

212 (20.9%)
362 (35.8%)

257 (26.3%)
425 (43.5%)

391 (39.1%)
547 (54.8%)

<0.001
<0.001

136
354
256
70
192
5
9
4
12

158
445
308
81
245
8
11
8
15

211
478
371
102
283
7
16
6
14

296
603
496
179
377
7
6
5
8

<0.001
<0.001
<0.001
<0.001
<0.001
0.900
0.153
0.713
0.502

(14.1%)
(36.6%)
(26.5%)
(7.2%)
(19.9%)
(0.5%)
(0.9%)
(0.4%)
(1.2%)

(15.6%)
(44%)
(30.4%)
(8%)
(24.2%)
(0.8%)
(1.1%)
(0.8%)
(1.5%)

(21.6%)
(48.9%)
(38%)
(10.4%)
(29%)
(0.7%)
(1.6%)
(0.6%)
(1.4%)

(29.6%)
(60.4%)
(49.6%)
(17.9%)
(37.7%)
(0.7%)
(0.6%)
(0.5%)
(0.8%)

CV cardiovascular; HF heart failure; MI myocardial infarction.

* Worsening heart failure was dened as death from heart failure, hospitalization for heart failure, or unscheduled medical ofce visit for heart failure.

collected, processed, and cross validated across 5 central

facilities.
sUA (mg/dl) was measured at the time of study enrollment (baseline, up to 48 hours after admission) and every 4
to 8 weeks up to 112 weeks postdischarge. There was little
evidence for nonlinearity in the relation between sUA and
clinical end points, across a physiological range of sUA.
Enrollment sUA levels were divided into quartiles and effect
sizes are presented in reference to quartile 1 (lowest). For
complete interaction analyses, sUA was treated as a
continuous function, and effect sizes are presented per
5 mg/dl increase in sUA. Serial postdischarge sUA levels
are presented by presence or absence of the primary end
points. The overall study design and nal analytical cohort
selection are displayed in Figure 1.
Demographic characteristics including self-reported race,
signs and/or symptoms of HF, vital signs, laboratory parameters, initial electrocardiographic ndings, medical history, and admission medications were compared across
quartiles of baseline sUA levels. Baseline characteristics and

clinical outcomes were also presented separately for men,

women, whites, and blacks. An independent blinded adjudication committee determined the specic causes of death
and reasons for rehospitalization. The present post hoc
analysis used the same 2 co-primary end points as the
overall EVEREST trial: all-cause mortality (ACM) and a
composite end point of cardiovascular mortality or HF
hospitalization. Secondary end points included other causes
of death and rehospitalization, worsening HF (dened as
death, hospitalization, or unplanned ofce visit for HF), and
combined cardiovascular mortality and rehospitalization.
Median follow-up in the EVEREST trial was 9.9 months
(interquartile range 5.3 to 16.1 months).
Continuous variables are expressed as mean  SD if
normally distributed and as median (interquartile range) if
non-normally distributed. Categorical variables are
expressed as number (%). Outcomes were assessed as time
to rst event using Cox proportional hazard models. KaplanMeier curves by sUA quartile were constructed for the both
primary end points and compared using log-rank tests. The

Heart Failure/Uric Acid and Hospitalized Heart Failure

Figure 3. Kaplan Meier curves. Event curves for ACM (A) and composite cardiovascular mortality and HF hospitalizations (B). Times to events were compared
using log-rank tests.

proportional hazards assumption (by Kolmogorov-type

supremum tests for nonproportionality) was upheld. Effect
sizes were reported as hazard ratios (HR) with 95% condence intervals (CI).
Multivariate models included 24 prespecied covariates
including tolvaptan treatment assignment, demographic
characteristics (age, gender, and region of origin), vital signs
on admission (supine systolic blood pressure), laboratory
testing (EF, serum sodium, blood urea nitrogen, and B-type

natriuretic peptide), initial admission electrocardiogram

(QRS duration and presence of atrial brillation), clinical
characteristics (ischemic HF origin, coronary artery disease,
diabetes, hypertension, chronic obstructive pulmonary
disease, chronic kidney disease [CKD], and New York Heart
Association class IV), and baseline medication use (allopurinol, angiotensin converting enzyme-inhibitors, angiotensin
II receptor blockers, b blockers, mineralocorticoid receptor
antagonists, digoxin, and intravenous inotropes).

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Figure 4. Forest plots. Univariate subgroup analyses for ACM (A) and composite cardiovascular (CV) mortality and HF hospitalizations (B). The p values are
displayed for each interaction term.

Figure 5. Changes in sUA levels over time. Baseline sUA was measured within 48 hours of hospital admission. The overall time course of mean sUA levels
over the 112 weeks follow-up has been stratied by the presence and absence of ACM (A) and composite cardiovascular (CV) mortality and HF hospitalizations (B).

Multiple imputation procedures (fully conditional

specication method) were used to impute any missing
covariate data (w28% for natriuretic peptides, 4% for
QRS duration, 2% for jugular venous distension, and
2% for all other variables). No evidence of signicant
collinearity between baseline sUA and the covariate set
was detected. Separate interaction analyses were performed for gender, race, estimated glomerular ltration
rate (eGFR) <30 ml/min/1.73 m2 (by the Modication of
Diet in Renal Disease formula), and admission allopurinol
use. This cutoff in eGFR was selected a priori because
sUA does not appear to predict further declines in renal
function in stage IV and V CKD18 and may be differentially associated with clinical end points in this population

compared with preserved or mildly impaired renal function.19,20 Because tolvaptan is known to increase sUA as
early as day 1 of hospitalization,15,17 treatment assignment
was also included as an interaction term. All statistical
analyses were performed using SAS version 9.2 (SAS
Institute Inc, Cary, North Carolina).
Results
Of the 4,133 patients enrolled in the EVEREST program,
178 patients had missing baseline sUA levels (4.3%) and
were excluded. The remaining cohort (n 3,955) was
divided into sUA quartiles Q1 (n 967, range 1.2 to
7.0 mg/dl), Q2 (n 1,012, range 7.1 to 8.8 mg/dl),

Heart Failure/Uric Acid and Hospitalized Heart Failure

Q3 (n 977, range 8.9 to 10.8 mg/dl), and Q4 (n 999,

range 10.9 to 21.0 mg/dl). sUA was normally distributed
with a mean of 9.1  2.8 mg/dl and median of 8.8 (interquartile range 7.1 to 10.9 mg/dl; Figure 2). sUA was higher
in men than in women (9.3  2.7 vs 8.7  3.0 mg/dl;
Supplementary Figure 1) and higher in blacks than in whites
(10.0  2.7 vs 9.0  2.8 mg/dl; Supplementary Figure 2).
Table 1 presents the baseline characteristics by sUA
quartiles. Patients in the highest sUA quartile were more
likely to be younger, men, black, and from North America
(all comparisons p <0.001). On admission, higher sUA was
associated with lower systolic and diastolic blood pressures
(p <0.001), higher heart rates (p 0.02), and lower EF
(p <0.001). Patients in the highest sUA quartiles had more
jugular venous distension and elevated natriuretic peptides
(both p <0.001). These patients more frequently had a
history of stage IV and V CKD with elevated blood urea
nitrogen and serum creatinine on admission (p <0.001).
Higher sUA was associated with less ischemic HF origin
(p 0.03), New York Heart Association class IV symptoms
(p <0.001), and increased previous coronary artery bypass
grafting and percutaneous coronary interventions
(p <0.001). Allopurinol was used in 440 patients at
admission, ranging from 15.4% in quartile 1 to 8.5% in
quartile 4 (p <0.001). Admission angiotensin converting
enzyme-inhibitor and angiotensin II receptor blocker use
was less frequently reported in higher sUA quartiles,
whereas intravenous inotrope use was higher (p <0.001 for
both). Similar patterns and trends were observed across
gender and race subgroups (Supplementary Tables 1 to 4).
There were a total of 1,040 ACM events and 1,627
composite end points (cardiovascular mortality or HF hospitalization) over the median follow-up timeframe of
9.9 months. Rates of ACM increased with increasing sUA
levels in a step-wise fashion from quartile 1 (18.6%) to
quartile 4 (39.1%, p <0.001; Table 2). Similarly, rates of the
composite end point increased from 30.3% to 54.8%
(p <0.001). Analysis of secondary end points revealed
similar trends of increasing event rates with higher sUA
levels for cardiovascular mortality, worsening HF, HF
mortality, and hospitalization (p <0.001 for all end points).
Rates of myocardial infarction, stroke morbidity, or mortality did not differ by sUA quartile. Times to rst event
were also signicantly different by the Kaplan-Meier
method across sUA quartiles for ACM (Figure 3; log rank
p <0.001) and the composite end point (Figure 3; log rank
p 0.004). Compared with the lowest quartile of sUA, the
adjusted hazard increased with higher sUA levels for ACM
(Q2: HR 1.14, 95% CI 0.96 to 1.34, p 0.129; Q3: HR
1.22, 95% CI 1.02 to 1.46, p 0.033; Q4: HR 1.33, 95% CI
1.10 to 1.61, p 0.004) and the composite end point (Q2:
HR 1.10, 95% CI 0.96 to 1.25, p 0.185; Q3: HR 1.23,
95% CI 1.07 to 1.43, p 0.005; Q4: HR 1.38, 95% CI 1.18
to 1.62, p <0.001). Tolvaptan assignment did not modify
the association between sUA and the primary outcomes,
ACM (interaction term p 0.31), and the composite end
point (interaction term p 0.45). Thus, even in a placeborestricted subgroup, sUA (per 5 mg/dl increase) was
robustly predictive of excess ACM (HR 1.75, 95% CI 1.51
to 2.02, p <0.001) and the composite end point (HR 1.69,
95% CI 1.50 to 1.90, p <0.001). Supplementary Figure 3

depicts the individual adjusted HR for increasing deciles

of sUA (p 0.007 for ACM trend and p <0.001 for
composite end point trend).
Figure 4 summarizes the unadjusted interaction analysis
for gender, race, renal function, and allopurinol use. In the
nal multivariate analysis, only renal function signicantly
inuenced the relation between sUA and clinical end points.
In patients with enrollment eGFR 30 ml/min/1.73 m2,
sUA (per 5 mg/dl increase) was strongly associated with
increased hazard of ACM (HR 1.44, 95% CI 1.22 to 1.69,
p <0.001) and the composite end point (HR 1.44, 95% CI
1.26 to 1.64; p <0.001). However, in patients with eGFR
<30 ml/min/1.73 m2, sUA (per 5 mg/dl increase) was not
related to neither ACM (HR 0.93, 95% CI 0.78 to 1.10,
p 0.393) nor the composite end point (HR 1.00, 95% CI
0.87 to 1.16, p 0.978).
When examining the temporal trends, sUA levels
continued to decrease postdischarge to approximately 8 mg/
dl at 112 weeks follow-up. sUA was consistently higher in
patients who experienced postdischarge clinical events than
in those who did not; these differences persisted into the late
postdischarge period (Figure 5).
Discussion
In this large contemporary cohort of patients hospitalized
for WCHF, approximately half of patients had sUA levels
>9.0 mg/dl. sUA levels decrease during hospitalization and
into the postdischarge period, consistently across race and
gender subgroups. sUA was higher in younger patients,
men, blacks, and in patients enrolled in North American
centers. Despite observed differences across these demographic subsets, gender and race did not modulate the
association between sUA and postdischarge outcomes.
Higher sUA was associated with markers of congestion,
poor renal function, lower EF, and more advanced functional class. After accounting for the baseline differences in
risk proles and multiple interaction terms, baseline sUA
was associated with worse clinical end points in patients
with eGFR 30 ml/min/1.73 m2 at the time of enrollment,
but not in those with eGFR <30 ml/min/1.73 m2.
To our knowledge, this is the largest study to date to
evaluate the prognostic use of sUA in patients hospitalized
for WCHF. Our data from the EVEREST trial provide a
number of advantages to the current literature: (1)
Comprehensive characterization of a high-risk cohort with a
high number of postdischarge events; (2) Global, multicenter patient sampling; (3) Robust multivariate analysis
including 24 clinical and laboratory parameters with limited
missing data; (4) Reliable assessment of sUA in a centralized core laboratory; (5) Serial, longitudinal measurement of
sUA levels; and (6) Specic interaction analyses for gender,
race, and renal function. Based on our study ndings, sUA
represents a strong, independent prognostic variable in patients with WCHF with relatively preserved baseline renal
function.
In a recent meta-analysis, incremental elevations in sUA
(by 1 mg/dL) increased the odds of incident HF by w19%
in the general population and increased risk of ACM by
w4% in patients with existing chronic HF.21 These ndings
have been extended to patients admitted for WCHF with

The American Journal of Cardiology (www.ajconline.org)

sUA measured in the emergency department,6 during hospitalization3,4,6e9,11 and predischarge5,10 strongly correlated
with in-hospital and postdischarge outcomes. A retrospective population-based study from Israel including 8,246
patients showed that the addition of laboratory parameters
including sUA improved 1-year mortality risk prediction.8
In 11,681 men enrolled in the Multiple Risk Factor Intervention Trial, WCHF admissions and increased diuretic
requirement were associated with increased sUA levels,
which improved with hospital discharge and diuretic
discontinuation.2 The decrease in mean sUA throughout the
postdischarge period seen in our study may be partially
explained by increased survivorship in patients with low
sUA levels. Most of these studies are limited by smaller
numbers of patients from single institutions, incomplete
statistical accounting, and short-term follow-up.
Enhanced xanthine oxidase activity, in response to hypoxia and inammation, appears to be a major source of
myocardial and vascular oxidative stress in patients with
HF. Consistently, sUA is signicantly associated with
several inammatory markers, including C-reactive protein
and interleukin-6 in chronic HF.22 Interestingly, UA itself is
associated with enhanced free-radical scavenging and
endothelium-dependent vasodilation in HF.23 However,
sUA may be a simple byproduct of xanthine oxidase
enzymatic upregulation, produced along with multiple
reactive oxygen species. Thus, sUA may serve as an
important index of impaired oxidative metabolism, which at
least partially mediates myocardial dysfunction and reduced
functional capacity.24
sUA was initially believed to represent simply a marker
of poor renal function.12 However, our data suggest that
sUA has differential prognostic use based on in-hospital
eGFR. These ndings corroborate data from a propensityscore matched analysis from the Beta-Blocker Evaluation
of Survival Trial showing that hyperuricemia was associated
with ACM and HF hospitalization only in patients with
chronic HF without CKD, but not in those with CKD.20 This
suggests that elevated sUA is associated with adverse outcomes, when it is a result of increased production rather than
decreased clearance alone.20 In fact, limited data have
demonstrated that sUA is at least partially secreted by the
failing myocardium in HF. In a small Japanese cohort,
the transcardiac gradient in sUA directly sampled from
the aortic root and coronary sinus increased with severity
of HF.25
Most sUA-lowering therapies (uricosuric) without
xanthine oxidase inhibition have not been shown to improve
clinical severity, functional capacity, hemodynamics, and
prognosis of patients with HF in large, prospectively conducted clinical studies.26 Accumulating data, supporting the
prognostic use of sUA in HF have made xanthine oxidaseinhibition an attractive therapeutic target. Treatment with
allopurinol in a large Israeli cohort of patients with chronic
HF was independently associated with improved survival at
median follow-up of 1.4 years.27 In contrast, the Oxypurinol
Compared With Placebo for Class III-IV NYHA Congestive
Heart Failure trial showed that treatment with oxypurinol
did not inuence composite morbidity and mortality at
24 weeks.28 A recent meta-analysis of 11 trials and over
20,000 subjects followed for 2 years showed that sUA

changes during pharmacologic treatment did not predict

cardiovascular outcomes.29 We await the results of the
recently completed EXACT-HF (Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients;
NCT00987415) trial, which is a multicenter randomized
24-week trial of allopurinol in hyperuricemic (sUA
9.5 mg/dl) patients with chronic HF with reduced EF.30
The post hoc nature of the present study makes the
ndings vulnerable to selection bias and confounding from
measured and unmeasured parameters. Robust multivariate
modeling may not be sufcient to account for the vast differences in clinical proles of patients with differing sUA
levels. The EVEREST population represents a highly
selected cohort and notably excluded patients with severe
CKD (serum creatinine >3.5 mg/dl). In WCHF, treatment
with diuretics has a known effect on sUA levels; however,
our multivariate models did not account for this parameter
given that >95% of patients were on diuretics before or
during hospitalization. Data regarding specic in-hospital
diuretic dosages and postdischarge allopurinol use were
not available for analysis. More data are required regarding
the prognostic use of sUA in HF with preserved EF and new
onset HF. Despite these limitations, this simple, inexpensive, widely available, reliably measured metric may serve
as a valuable predictive biomarker, beyond traditional
markers of prognosis. The differences in sUA levels and
attendant prognostic use in important patient subgroups may
inform selection in future clinical trials. Our hypothesisgenerating work calls for a prospective, randomized,
controlled trial evaluating xanthine oxidase-inhibition in the
high-risk population of patients hospitalized for WCHF.
Disclosures
The author Haris P. Subacius conducted all nal analyses
for this manuscript with funding from the Center for Cardiovascular Innovation (Northwestern University Feinberg
School of Medicine, Chicago, Illinois). The authors had full
access to the data, take responsibility for its integrity, and
had complete control and authority over manuscript preparation and the decision to publish. Dr. Mentz has received
research support from Gilead and honoraria from Thoratec,
HeartWare, BMS, and Novartis. Dr. Chioncel has received
research support from Abbott, Servier, and Vifor and served
as member on the Steering Committee of studies sponsored
by Novartis. Dr. Maggioni served as member on the
Steering Committee of studies sponsored by Bayer,
Novartis, Otsuka, Cardiorentis, and Abbott Vascular.
Dr. Zannad has had principal relation with Cardiorenal
Diagnostics, served as a consultant for Air Liquide, St.
Judes Medical, Boston Scientic, Servier, Novartis, and
participated as a committee member for Takeda Pharmaceuticals, BIOTRONIK, Janssen, ResMed, Bayer, and
Pzer. Dr. Konstam discloses research support and/or
consulting fees from Otsuka, Amgen, Johnson & Johnson
Services, Inc., and Novartis. Dr. Givertz discloses funding
related to the NIH/NHLBI HF Network. Dr. Butler has
received research support from the National Institutes of
Health, European Union, Health Resources and Services
Administration, U.S. Food and Drug Administration,
and served as a consultant for Amgen, Bayer, Celladon,

Heart Failure/Uric Acid and Hospitalized Heart Failure

Gambro, GE Healthcare, Janssen, Medtronic, Novartis,

Ono, Relypsa, and Trevena. Dr. Gheorghiade has been a
consultant for Abbott Laboratories, Astellas, AstraZeneca,
Bayer HealthCare AG, Corthera, Cytokinetics, Debiopharm
S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria,
Johnson & Johnson, Medtronic, Merck, Novartis Pharma
AG, Otsuka Pharmaceuticals, Palatin Technologies, PeriCor
Therapeutics, Protein Design Laboratories, Sano-Aventis,
Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical, and Trevena Therapeutics. All other authors have no
conicts of interest to declare.
Supplementary Data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
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