Relation of Serum Uric Acid Levels and Outcomes AmongPatients Hospitalized for Worsening Heart Failure With

Reduced Ejection Fraction (from the Efcacy of VasopressinAntagonism 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

ted wng cracesUArimaheabasend wthan

Hospitalizat(WCHF) is abations in cliniSerum uric aciwith WCHFfollowed ambConsistently, s

tion,12 race,13

f Vasopressinith Tolvaptanailed, longitu-nical parame-F. Thus, webetween sUA

0002-9149 online.org

http://dx.doi.org/10.1016/j.amjcard.2014.09.008ufts Medical Center, Boston, Massachusetts; kDipartimento E-mail address: muthu@md.northwestern.edu (M. Vadugana

/14/$ - see front matter 2014 Elsevier Inc. All rights reserved. www.ajcof adverse prognosis in the setting of WCHF. sUA may at the time of enrollment and clinical characteristics and

aDepartment of Medicine, Massachusetts General Hospital, Boston,Massachusetts; bCenter for Cardiovascular Innovation, NorthwesternUniversity Feinberg School of Medicine, Chicago, Illinois; cDepartment ofMedicine, Stanford University School of Medicine, Stanford, California;dDuke University Medical Center, Durham, North Carolina; eDivision ofCardiology, Department of Medicine, Northwestern University FeinbergSchool of Medicine, Chicago, Illinois; fInstitute of Emergency forCardiovascular Diseases Prof. C.C. Iliescu, Cardiology, Bucharest,Romania; gResearch Center of the Italian Association of Hospital Cardi-ologists (ANMCO), Florence, Italy; hUniversity of Gothenburg, Gothen-burg, Sweden; iDepartment of Cardiology, Nancy University, Nancy,France; jT

Cardiovascolare, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo,Italy; lCardiovascular Division, Brigham and Womens Hospital, HarvardMedical School, Boston, Massachusetts; and mDivision of Cardiology,Emory University School of Medicine, Atlanta, Georgia. Manuscriptreceived July 21, 2014; revised manuscript received and acceptedSeptember 2, 2014.

Otsuka Inc. (Rockville, Maryland) provided nancial and materialsupport for the EVEREST trial. Database management was performed bythe sponsor.

See page 8 for disclosure information.*Corresponding author: Tel: (832) 725-7222; fax: (617) 726-6861.

than).natriuretic peptides, and more impaired renal function. After accounting for 24 baselinecovariates, 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

ardio2 The American Journal of Cpostdischarge outcomes in patients hospitalized for WCHFwith reduced ejection fraction (EF).

Methods

The study design16 and primary results15,17 of theEVEREST trial have been previously described. In brief,EVEREST was a global, multicenter, double-blinded, pla-cebo-controlled randomized trial examining tolvaptan, anoral vasopressin-2 receptor antagonist. Patients eligible forenrollment were 18 years of age, hospitalized for WCHF

Figure 1. Overall study design and analytical cohort selection. LVEF left

Figure 2. Distribution and descriptive statistics of sUA levels. The primary predictoof approximately 9 mg/dl. The black curve represents the normal density distribsample. IQR interquartile range.logy (www.ajconline.org)with New York Heart Association III-IV functional status,EF 40% and presenting with 2 signs or symptoms ofvolume overload. Relevant exclusion criteria include serumcreatinine >3.5 mg/dl; subjects currently treated withhemoltration or dialysis; refractory, end-stage HF; or a lifeexpectancy

Table 1Baseline characteristics by serum uric acid quartile

Variable Baseline Serum Uric Acid Quartiles p-value

I(n967)

II(n1,012)

III(n977)

IV(n999)

Serum uric acid, (mg/dL), meanSD 5.81 80.5 9.80.6 12.91.8Serum uric acid, (mg/dL), range 1.2-7.0 7.1-8.8 8.9-10.8 10.9-21.0Tolvaptan assignment 514 (53.2%) 494 (48.8%) 464 (47.5%) 504 (50.5%) 0.073Age (years), meanSD 67.110.7 66.111.8 65.412 64.512.7

8754

3

I rece

ral ed

ardioTable 1(continued)

Variable

I(n967)

ACEI/ ARB 823 (85.3%)Beta-Blockers 667 (69.1%)Mineralocorticoid receptor antagonists 511 (53%)Digoxin 438 (45.4%)Intravenous Inotropes 33 (3.4%)Statin 345 (35.8%)

ACEI angiotensin converting enzyme inhibitor; ARB angiotensin INYHA New York Heart Association; SD standard deviation.* Peripheral edema was dened as slight/ moderate/ marked pedal or sac Glomerular ltration rate estimated by Cockcroft-Gault formula.

Table 2

4 The American Journal of Ccollected, processed, and cross validated across 5 centralfacilities.

sUA (mg/dl) was measured at the time of study enroll-ment (baseline, up to 48 hours after admission) and every 4to 8 weeks up to 112 weeks postdischarge. There was littleevidence for nonlinearity in the relation between sUA andclinical end points, across a physiological range of sUA.Enrollment sUA levels were divided into quartiles and effectsizes are presented in reference to quartile 1 (lowest). Forcomplete interaction analyses, sUA was treated as acontinuous function, and effect sizes are presented per5 mg/dl increase in sUA. Serial postdischarge sUA levelsare presented by presence or absence of the primary endpoints. The overall study design and nal analytical cohortselection are displayed in Figure 1.

Demographic characteristics including self-reported race,signs and/or symptoms of HF, vital signs, laboratory pa-rameters, initial electrocardiographic ndings, medical his-tory, and admission medications were compared acrossquartiles of baseline sUA levels. Baseline characteristics and

Causes of death and rehospitalization by baseline serum uric acid quartile

Baseli

I(n967)

II(n1

Serum uric acid, (mg/dL), mean (SD) 5.81 8Serum uric acid, (mg/dL), range 1.2-7.0 7.1-Primary EndpointsAll-cause mortality 180 (18.6%) 212 (2CV mortality HF hospitalization 293 (30.3%) 362 (3Secondary EndpointsCV mortality 136 (14.1%) 158 (1CV mortality CV hospitalization 354 (36.6%) 445 (4Worsening HF * 256 (26.5%) 308 (3HF mortality 70 (7.2%) 81 (8HF hospitalization 192 (19.9%) 245 (2MI mortality 5 (0.5%) 8 (0MI hospitalization 9 (0.9%) 11 (1Stroke mortality 4 (0.4%) 8 (0Stroke hospitalization 12 (1.2%) 15 (1

CV cardiovascular; HF heart failure; MI myocardial infarction.* Worsening heart failure was dened as death from heart failure, hospitalizatiBaseline Serum Uric Acid Quartiles p-value

II(n1,012)

III(n977)

IV(n999)

80 (87.1%) 837 (85.8%) 796 (79.9%)

nd HHeart Failure/Uric Acid aproportional hazards assumption (by Kolmogorov-typesupremum tests for nonproportionality) was upheld. Effectsizes were reported as hazard ratios (HR) with 95% con-dence intervals (CI).

Multivariate models included 24 prespecied covariatesincluding tolvaptan treatment assignment, demographiccharacteristics (age, gender, and region of origin), vital signson admission (supine systolic blood pressure), laboratorytesting (EF, serum sodium, blood urea nitrogen, and B-type

Figure 3. Kaplan Meier curves. Event curves for ACM (A) and composite cardiovausing log-rank tests.ospitalized Heart Failure 5natriuretic peptide), initial admission electrocardiogram(QRS duration and presence of atrial brillation), clinicalcharacteristics (ischemic HF origin, coronary artery disease,diabetes, hypertension, chronic obstructive pulmonarydisease, chronic kidney disease [CKD], and New York HeartAssociation class IV), and baseline medication use (allopu-rinol, angiotensin converting enzyme-inhibitors, angiotensinII receptor blockers, b blockers, mineralocorticoid receptorantagonists, digoxin, and intravenous inotropes).

scular mortality and HF hospitalizations (B). Times to events were compared

ardio6 The American Journal of CMultiple imputation procedures (fully conditionalspecication method) were used to impute any missingcovariate data (w28% for natriuretic peptides, 4% forQRS duration, 2% for jugular venous distension, and2% for all other variables). No evidence of signicantcollinearity between baseline sUA and the covariate setwas detected. Separate interaction analyses were per-formed for gender, race, estimated glomerular ltrationrate (eGFR)

nd HQ3 (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 distributedwith a mean of 9.1 2.8 mg/dl and median of 8.8 (inter-quartile range 7.1 to 10.9 mg/dl; Figure 2). sUA was higherin 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 sUAquartiles. Patients in the highest sUA quartile were morelikely to be younger, men, black, and from North America(all comparisons p

ardiosUA measured in the emergency department,6 during hos-pitalization3,4,6e9,11 and predischarge5,10 strongly correlatedwith in-hospital and postdischarge outcomes. A retrospec-tive population-based study from Israel including 8,246patients showed that the addition of laboratory parametersincluding sUA improved 1-year mortality risk prediction.8

In 11,681 men enrolled in the Multiple Risk Factor Inter-vention Trial, WCHF admissions and increased diureticrequirement were associated with increased sUA levels,which improved with hospital discharge and diureticdiscontinuation.2 The decrease in mean sUA throughout thepostdischarge period seen in our study may be partiallyexplained by increased survivorship in patients with lowsUA levels. Most of these studies are limited by smallernumbers of patients from single institutions, incompletestatistical accounting, and short-term follow-up.

Enhanced xanthine oxidase activity, in response to hyp-oxia and inammation, appears to be a major source ofmyocardial and vascular oxidative stress in patients withHF. Consistently, sUA is signicantly associated withseveral inammatory markers, including C-reactive proteinand interleukin-6 in chronic HF.22 Interestingly, UA itself isassociated with enhanced free-radical scavenging andendothelium-dependent vasodilation in HF.23 However,sUA may be a simple byproduct of xanthine oxidaseenzymatic upregulation, produced along with multiplereactive oxygen species. Thus, sUA may serve as animportant index of impaired oxidative metabolism, which atleast partially mediates myocardial dysfunction and reducedfunctional capacity.24

sUA was initially believed to represent simply a markerof poor renal function.12 However, our data suggest thatsUA has differential prognostic use based on in-hospitaleGFR. These ndings corroborate data from a propensity-score matched analysis from the Beta-Blocker Evaluationof Survival Trial showing that hyperuricemia was associatedwith ACM and HF hospitalization only in patients withchronic HF without CKD, but not in those with CKD.20 Thissuggests that elevated sUA is associated with adverse out-comes, when it is a result of increased production rather thandecreased clearance alone.20 In fact, limited data havedemonstrated that sUA is at least partially secreted by thefailing myocardium in HF. In a small Japanese cohort,the transcardiac gradient in sUA directly sampled fromthe aortic root and coronary sinus increased with severityof HF.25

Most sUA-lowering therapies (uricosuric) withoutxanthine oxidase inhibition have not been shown to improveclinical severity, functional capacity, hemodynamics, andprognosis of patients with HF in large, prospectively con-ducted clinical studies.26 Accumulating data, supporting theprognostic use of sUA in HF have made xanthine oxidase-inhibition an attractive therapeutic target. Treatment withallopurinol in a large Israeli cohort of patients with chronicHF was independently associated with improved survival atmedian follow-up of 1.4 years.27 In contrast, the OxypurinolCompared With Placebo for Class III-IV NYHA CongestiveHeart Failure trial showed that treatment with oxypurinoldid not inuence composite morbidity and mortality at

28

8 The American Journal of C24 weeks. A recent meta-analysis of 11 trials and over20,000 subjects followed for 2 years showed that sUAchanges during pharmacologic treatment did not predictcardiovascular outcomes.29 We await the results of therecently completed EXACT-HF (Xanthine Oxidase Inhibi-tion for Hyperuricemic Heart Failure Patients;NCT00987415) trial, which is a multicenter randomized24-week trial of allopurinol in hyperuricemic (sUA9.5 mg/dl) patients with chronic HF with reduced EF.30

The post hoc nature of the present study makes thendings vulnerable to selection bias and confounding frommeasured and unmeasured parameters. Robust multivariatemodeling may not be sufcient to account for the vast dif-ferences in clinical proles of patients with differing sUAlevels. The EVEREST population represents a highlyselected cohort and notably excluded patients with severeCKD (serum creatinine >3.5 mg/dl). In WCHF, treatmentwith diuretics has a known effect on sUA levels; however,our multivariate models did not account for this parametergiven that >95% of patients were on diuretics before orduring hospitalization. Data regarding specic in-hospitaldiuretic dosages and postdischarge allopurinol use werenot available for analysis. More data are required regardingthe prognostic use of sUA in HF with preserved EF and newonset HF. Despite these limitations, this simple, inexpen-sive, widely available, reliably measured metric may serveas a valuable predictive biomarker, beyond traditionalmarkers of prognosis. The differences in sUA levels andattendant prognostic use in important patient subgroups mayinform selection in future clinical trials. Our hypothesis-generating work calls for a prospective, randomized,controlled trial evaluating xanthine oxidase-inhibition in thehigh-risk population of patients hospitalized for WCHF.

Disclosures

The author Haris P. Subacius conducted all nal analysesfor this manuscript with funding from the Center for Car-diovascular Innovation (Northwestern University FeinbergSchool of Medicine, Chicago, Illinois). The authors had fullaccess to the data, take responsibility for its integrity, andhad complete control and authority over manuscript prepa-ration and the decision to publish. Dr. Mentz has receivedresearch support from Gilead and honoraria from Thoratec,HeartWare, BMS, and Novartis. Dr. Chioncel has receivedresearch support from Abbott, Servier, and Vifor and servedas member on the Steering Committee of studies sponsoredby Novartis. Dr. Maggioni served as member on theSteering Committee of studies sponsored by Bayer,Novartis, Otsuka, Cardiorentis, and Abbott Vascular.Dr. Zannad has had principal relation with CardiorenalDiagnostics, served as a consultant for Air Liquide, St.Judes Medical, Boston Scientic, Servier, Novartis, andparticipated as a committee member for Takeda Pharma-ceuticals, BIOTRONIK, Janssen, ResMed, Bayer, andPzer. Dr. Konstam discloses research support and/orconsulting fees from Otsuka, Amgen, Johnson & JohnsonServices, Inc., and Novartis. Dr. Givertz discloses fundingrelated to the NIH/NHLBI HF Network. Dr. Butler hasreceived research support from the National Institutes ofHealth, European Union, Health Resources and Services

logy (www.ajconline.org)Administration, U.S. Food and Drug Administration,and served as a consultant for Amgen, Bayer, Celladon,

hyperuricemic heart failure patients: design and rationale of the

nd HGambro, GE Healthcare, Janssen, Medtronic, Novartis,Ono, Relypsa, and Trevena. Dr. Gheorghiade has been aconsultant for Abbott Laboratories, Astellas, AstraZeneca,Bayer HealthCare AG, Corthera, Cytokinetics, DebiopharmS.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria,Johnson & Johnson, Medtronic, Merck, Novartis PharmaAG, Otsuka Pharmaceuticals, Palatin Technologies, PeriCorTherapeutics, Protein Design Laboratories, Sano-Aventis,Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceu-tical, and Trevena Therapeutics. All other authors have noconicts of interest to declare.

Supplementary Data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.amjcard.2014.09.008.

1. Gheorghiade M, Pang PS, Ambrosy AP, Lan G, Schmidt P, FilippatosG, Konstam M, Swedberg K, Cook T, Traver B, Maggioni A, Burnett J,Grinfeld L, Udelson J, Zannad F. A comprehensive, longitudinaldescription of the in-hospital and post-discharge clinical, laboratory,and neurohormonal course of patients with heart failure who die or arere-hospitalized within 90 days: analysis from the EVEREST trial. HeartFail Rev 2012;17:485e509.

2. Misra D, Zhu Y, Zhang Y, Choi HK. The independent impact ofcongestive heart failure status and diuretic use on serum uric acidamong men with a high cardiovascular risk prole: a prospectivelongitudinal study. Semin Arthritis Rheum 2011;41:471e476.

3. Alimonda AL, Nunez J, Nunez E, Husser O, Sanchis J, Bodi V, MinanaG, Robles R, Mainar L, Merlos P, Darmofal H, Llacer A. Hyperuri-cemia in acute heart failure. More than a simple spectator? Eur J InternMed 2009;20:74e79.

4. Cengel A, Turkoglu S, Turfan M, Boyaci B. Serum uric acid levels as apredictor of in-hospital death in patients hospitalized for decom-pensated heart failure. Acta Cardiol 2005;60:489e492.

5. Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M, Goto K, Goto D,Yokota T, Kinugawa S, Yokoshiki H, Takeshita A, Tsutsui H; In-vestigators J-C. Hyperuricemia predicts adverse outcomes in patientswith heart failure. Int J Cardiol 2011;151:143e147.

6. Henry-Okafor Q, Collins SP, Jenkins CA, Miller KF, Maron DJ,Naftilan AJ, Weintraub N, Fermann GJ, McPherson J, Menon S,Sawyer DB, Storrow AB. Relationship between uric acid levels anddiagnostic and prognostic outcomes in acute heart failure. Open Bio-mark J 2012;5:9e15.

7. Malek F, Ostadal P, Parenica J, Jarkovsky J, Vitovec J, Widimsky P,Linhart A, Fedorco M, Coufal Z, Miklik R, Kruger A, Vondrakova D,Spinar J. Uric acid, allopurinol therapy, and mortality in patientswith acute heart failureeresults of the Acute HEart FAilure Databaseregistry. J Crit Care 2012;27:737.e11e737.e24.

8. Novack V, Pencina M, Zahger D, Fuchs L, Nevzorov R, Jotkowitz A,Porath A. Routine laboratory results and thirty day and one-yearmortality risk following hospitalization with acute decompensatedheart failure. PLoS One 2010;5:e12184.

9. Park HS, Kim H, Sohn JH, Shin HW, Cho YK, Yoon HJ, Nam CW,Hur SH, Kim YN, Kim KB, Park HJ. Combination of uric acid andNT-ProBNP: a more useful prognostic marker for short-term clinicaloutcomes in patients with acute heart failure. Korean J Intern Med2010;25:253e259.

10. Pascual-Figal DA, Hurtado-Martinez JA, Redondo B, Antolinos MJ,Ruiperez JA, Valdes M. Hyperuricaemia and long-term outcome afterhospital discharge in acute heart failure patients. Eur J Heart Fail2007;9:518e524.

11. Wasserman A, Shnell M, Boursi B, Guzner-Gur H. Prognosticsignicance of serum uric acid in patients admitted to the Departmentof Medicine. Am J Med Sci 2010;339:15e21.

12. Tian Y, Chen Y, Deng B, Liu G, Ji ZG, Zhao QZ, Zhen YZ, Gao YQ,Tian L, Wang L, Ji LS, Ma GP, Liu KS, Liu C. Serum uric acid as an

Heart Failure/Uric Acid aindex of impaired renal function in congestive heart failure. J GeriatrCardiol 2012;9:137e142.13. Maynard JW, McAdams-Demarco MA, Law A, Kao L, Gelber AC,Coresh J, Baer AN. Racial differences in gout incidence in apopulation-based cohort: Atherosclerosis Risk in Communities Study.Am J Epidemiol 2014;179:576e583.

14. Puig JG, Michan AD, Jimenez ML, Perez de Ayala C, Mateos FA,Capitan CF, de Miguel E, Gijon JB. Female gout. Clinical spectrumand uric acid metabolism. Arch Intern Med 1991;151:726e732.

15. Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, MaggioniAP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, ZimmerC, Orlandi C. Short-term clinical effects of tolvaptan, an oralvasopressin antagonist, in patients hospitalized for heart failure: theEVEREST Clinical Status Trials. JAMA 2007;297:1332e1343.

16. Gheorghiade M, Orlandi C, Burnett JC, Demets D, Grinfeld L,Maggioni A, Swedberg K, Udelson JE, Zannad F, Zimmer C, KonstamMA. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efcacy ofVasopressin antagonism in Heart Failure: Outcome Study withTolvaptan (EVEREST). J Card Fail 2005;11:260e269.

17. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, MaggioniAP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, ZimmerC, Orlandi C. Effects of oral tolvaptan in patients hospitalized forworsening heart failure: the EVEREST Outcome Trial. JAMA2007;297:1319e1331.

18. Nacak H, van Diepen M, de Goeij MC, Rotmans JI, Dekker FW. Uricacid: association with rate of renal function decline and time until startof dialysis in incident pre-dialysis patients. BMC Nephrol 2014;15:91.

19. Sato T, Yamauchi H, Suzuki S, Yoshihisa A, Yamaki T, Sugimoto K,Kunii H, Nakazato K, Suzuki H, Saitoh S, Takeishi Y. Distinct prog-nostic factors in patients with chronic heart failure and chronic kidneydisease. Int Heart J 2013;54:311e317.

20. Filippatos GS, Ahmed MI, Gladden JD, Mujib M, Aban IB, Love TE,Sanders PW, Pitt B, Anker SD, Ahmed A. Hyperuricaemia, chronickidney disease, and outcomes in heart failure: potential mechanisticinsights from epidemiological data. Eur Heart J 2011;32:712e720.

21. Huang H, Huang B, Li Y, Huang Y, Li J, Yao H, Jing X, Chen J, WangJ. Uric acid and risk of heart failure: a systematic review and meta-analysis. Eur J Heart Fail 2014;16:15e24.

22. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ,Poole-Wilson PA, Coats AJ. Uric acid in chronic heart failure: a markerof chronic inammation. Eur Heart J 1998;19:1814e1822.

23. Alcaino H, Greig D, Chiong M, Verdejo H, Miranda R, Concepcion R,Vukasovic JL, Diaz-Araya G, Mellado R, Garcia L, Salas D, GonzalezL, Godoy I, Castro P, Lavandero S. Serum uric acid correlates withextracellular superoxide dismutase activity in patients with chronicheart failure. Eur J Heart Fail 2008;10:646e651.

24. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP,Stevenson JC, Coats AJ. Serum uric acid as an index of impairedoxidative metabolism in chronic heart failure. Eur Heart J 1997;18:858e865.

25. Sakai H, Tsutamoto T, Tsutsui T, Tanaka T, Ishikawa C, Horie M.Serum level of uric acid, partly secreted from the failing heart, is aprognostic marker in patients with congestive heart failure. Circ J2006;70:1006e1011.

26. Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, KinugawaT, Igawa O, Hisatome I, Shigemasa C, Anker SD, Doehner W. Uricacid-lowering treatment with benzbromarone in patients with heartfailure: a double-blind placebo-controlled crossover preliminary study.Circ Heart Fail 2010;3:73e81.

27. Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levelsand allopurinol use in chronic heart failure: association with improvedsurvival. J Card Fail 2012;18:694e701.

28. Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, ColucciWS, Mann DL, Liu P, Givertz MM, Schwarz RP; Investigators O-C.Impact of oxypurinol in patients with symptomatic heart failure. Re-sults of the OPT-CHF study. J Am Coll Cardiol 2008;51:2301e2309.

29. Savarese G, Ferri C, Trimarco B, Rosano G, Dellegrottaglie S, LoscoT, Casaretti L, DAmore C, Gambardella F, Prastaro M, Rengo G,Leosco D, Perrone-Filardi P. Changes in serum uric acid levels andcardiovascular events: a meta-analysis. Nutr Metab Cardiovasc Dis2013;23:707e714.

30. Givertz MM, Mann DL, Lee KL, Ibarra JC, Velazquez EJ, HernandezAF, Mascette AM, Braunwald E. Xanthine oxidase inhibition for

ospitalized Heart Failure 9EXACT-HF study. Circ Heart Fail 2013;6:862e868.

Relation of Serum Uric Acid Levels and Outcomes Among Patients Hospitalized for Worsening Heart Failure With Reduced Ejecti ...MethodsResultsDiscussionDisclosuresSupplementary DataReferences