DOI: 10.1161/CIRCULATIONAHA.114.014536

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The EXACT-HF Study Running title: Givertz et al.; Allopurinol in High-Risk Heart Failure: EXACT-HF Michael M. Givertz, MD1; Kevin J. Anstrom, PhD2; Margaret M. Redfield, MD3; Anita Deswal, MD, MPH4; Haissam Haddad, MD5; Javed Butler, MD, MPH6; W.H. Wilson Tang, MD7; Mark E. Dunlap, MD8; Martin M. LeWinter, MD9; Douglas L. Mann, MD10; G. Michael Felker, MD2; Christopher M. O'Connor, MD2; Steven R. Goldsmith, MD11; Elizabeth O. Ofili, MD, MPH12; Mitchell T. Saltzberg, MD13; Kenneth B. Margulies, MD14; Thomas P. Cappola, pp , MD14; Marvin A. Konstam,, MD15; Marc J. Semigran, g , MD16; Steven E. 2 2 17 McNulty, MS ; Kerry L. Lee, PhD ; Monica R. Shah, MD, MSH ; Adrian F. He Hern Hernandez, rnan rn ande an dez, de z M z, MD D2 for the NHLBI Heart Failure Clinical Research Network* 1

Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 2Duke University Me Medical ediica call Ce C Center, n er,, Du nt D Durham, rham, NC; 3Mayo Clinic, Rochester, Roc oche oc h ster, MN; 4Michae he Michael aeel E. E DeBakey VA Medica Medical 5 Center, Cent Ce nter, Ba Bay Baylor ylor C College olleege ooff M Medicine, e iccin ed i e, e H Houston, ouston on, TX TX; Ot Ottawa Otta tawa H Heart eart IInstitute, ea nsti ns titutee, Ottawa, O tawaa, Canada; Ot Ca 6 Em Emory Univ Un University, iveersi ersi sity y, At Atla Atlanta, lant la nta, nt a, G GA; A; 7Cl Cleveland Clev vellan a d Cl Clin Clinic, iniic, Cl Clev Cleveland, evel ev elan el an nd, O OH; H; 8M MetroHealth etr trroH oHea ealt ea lthh Ca lt Camp Campus mpus mp u ooff us 9 Ca Western Case nR Reserve eseerve U University, nivversit ity, y, C Cleveland, levellannd, OH OH; Un University Univ iveersitty of iv of Vermont, Vermont ont, B Burlington, urrliing ngto tonn, V VT; T; 10 0 Washington Wash Wa hingt g on U University, nive ni verrsitty, S St. t. L t. Louis, ouis ou iss, MO MO;; 11He Hennepin Henn nnep epin ep in County Cou ounntyy Medical Meddical Center, Centterr, Minneapolis, Cent M nn Mi nneaapooli l s, MN; MN 12 Morehouse More Mo reho re houuse ho use School Scho Sc hool ho ol ooff M Medicine, edi dici cine ci ne,, At ne Atla Atlanta, lant la ntaa, nt a, G GA; A; 1133Chri Christiana C hri rist stia st iana ia na C Care arre He Heal Health alth al th S System, yste ys tem, te m, N Newark, ewar ew ark, ar k D k, DE; E E; 1144 University Univ Un iver iv ersi er sity si ty ooff Pe Penn Pennsylvania, nnsy nn sylv sy lvaani lv niaa, P Philadelphia, hila hi lade la delp de lphi lp hiaa, P hi PA; A; 15Tu Tufts Tuft ftss Me ft Medi Medical dica di call Center, ca Cent Ce nter nt er, Bo er Bost Boston, ston st on, MA; on MA; 16 Massachusetts Massachu huse hu sett se t s Ge tt Gene General nera ne rall Ho H Hospital, spit sp i all, Bo it Bost Boston, sttonn, MA MA;; 177Na National Nati tion ti onal a H al Heart, eart rt, Lu rt Lung Lung, ng, an ng andd Bl Bloo Blood oodd Institute, oo Bethesda, MD *A complete listing of the EXACT members, investigators and committees can be found in the Supplemental Material Address for Correspondence: Michael M. Givertz, MD Cardiovascular Division Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 Tel: 617-525-7052 Fax: 617-264-5265 E-mail: [email protected] Journal Subject Codes: Heart failure:[110] Congestive, Treatment:[118] Cardiovascular pharmacology, Myocardial biology:[91] Oxidant stress

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DOI: 10.1161/CIRCULATIONAHA.114.014536

Abstract

Background—Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results—We randomized 253 patients with symptomatic HF, left ventricular ejection fraction (LVEF) ”40%, and serum uric acid levels •9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite endpoint at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary endpoints included change in quality of life, submaximal exercise capacity, and LVEF. Uric acid levels were significantly reduced with allopurinol compared to placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 p y, both P250 pg/ml or N-terminal pro-B-type natriuretic

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DOI: 10.1161/CIRCULATIONAHA.114.014536

peptide [NT-pro-BNP] >1500 pg/ml).22 Patients with estimated glomerular filtration rate (eGFR) 2 to ”3 mg/dL) was also performed. Changes from baseline in KCCQ scores, 6MWT distances, echocardiographic measures, and biomarkers between the 2 treatment groups were assessed at 12 and 24 weeks with adjustment for the baseline value using an analysis of covariance approach. Missing values were handled using multiple imputation for all endpoints except echocardiographic measures. For the KCCQ overall summary score (9% missing data at 24 weeks), a total of 100 imputed data sets were used. The imputation model includes covariates for assigned treatment, renal ren nal al function funnct ctio ionn at io a baseline, age, gender and non-missing values for each of the KCCQ summary scores across all visits where KCCQ 6MWT missing vi isiits w here he re K CC CQ was completed. For the 6MW WT (20% missin ng data taa aatt 24 weeks), a similar imputation approach adjustments for walk mputation pu app ppro ro oach wa wass us used ed aand ndd iincluded nclu nc ludedd ad djusstm mennts nts fo or non nnon-missing on-m missin miss i g wa in alk k ddistances istaanc is n es e aatt eac eeach ac h time ime period. per e io iodd. d. Cumulative Cum mulat ulatiive ive event even ev en nt rates rate ra tess for te for death deat de ath and at and hospitalization hosppittal hosp aliz izat iz atio at i n were io weree estimated esstim stim matted e using using sing g the thhe he Kaplan–Meier Kaplan–Mei ierr method. met etho h d. ho d 28 F For or bbinary in nar a y ou outcomes, utc t om omes es,, od es odds dds rratios attio ioss and and 95% 9 % confidence 95 conf co nfid nf iden id e ce in en inte intervals terv te r als (CI) rv were obtained from logistic regression models. Hazard ratios (HR), 95% CI, and P-values for the comparison of the 2 treatment groups were determined with the use of the Cox regression model.29 A 2-sided alpha level of 0.05 was considered to indicate statistical significance. All data analyses were conducted with SAS software, version 9.2 or higher.

Results Patients 253 patients were enrolled between May 2010 and June 2013 at 38 sites in the United States and

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DOI: 10.1161/CIRCULATIONAHA.114.014536

Canada. Baseline demographic and clinical characteristics of the two treatment groups were similar (Table 1). The median (25th, 75th percentile) age of the study population was 63 (53, 72) years and median LVEF was 25% (19, 33). 82% were men and 29% were black. Patients had mild-moderate symptoms of chronic HF (median duration 5.2 [1.9, 10.1] years). Frequent comorbidities included diabetes mellitus 55%, hypertension 78%, and atrial fibrillation or flutter 49%. Hospitalization for HF in the past year was seen in 57%. Median UA level for the entire cohort was 11.1 (10.1, 12.1) mg/dL, and 23% of patients had a history of gout. Most patients were receiving guideline-recommended pharmacologic and device-based therapies, and were clinically stable (absence of rales 95%, trace or no edema 86%, jugular venous pressure 2 to ”3 mg/dL, the maximum target dose of 300 mg was achieved in 65% and 75%, respectively. For patients who permanently discontinued study drug, the median duration of treatment was 7.2 (2.6, 18.1) weeks. The final dose that patients were taking in the 2 treatment groups, stratified by baseline renal function, is provided in Supplemental Table 3. Primary endpoint At 24 weeks, there was no significant difference in the primary CCE between the allopurinol and

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DOI: 10.1161/CIRCULATIONAHA.114.014536

placebo-treated patients (worsened 45% vs. 46%, unchanged 42% vs. 34%, improved 13% vs. 19%, respectively; P=0.68) (Figure 2A). A pre-specified analysis of the primary CCE stratified by baseline serum creatinine level (”2 mg/dL [N=217] vs. >2 to ”3 mg/dL [N=36]) also showed no significant differences between the 2 groups (P=0.73 and P=1.00, respectively). Finally, a “per protocol” analysis that included only patients that were still taking study drug at the end of the study (or at the time of death) showed no difference in the primary CCE between groups (P=0.27). Secondary endpoints At 12 and 24 weeks, there was no significant difference in changes in KCCQ overall summary score Figure core or 6MWT distance between the allopurinol and placebo-treated patients (Table (Ta Ta abl ble 22,, Fi Figu gure gu r 3). Sensitivity analyses using observed data and worst-rank score analysis did not alter the results. There was endpoints KCCQ esuult ltss. s. T here he ree w as llittle i tle change in these endpoint it ntss oover nt ver the study pperiod: erio od: K CCQ median summary score, 76.6], (44.5, 6MWT median ummary mm scor re, e 660.7 0.77 [3 [[39.1, 9.11, 9. 1, 774.5], 4.5] 4. 5], 63 63.88 [[45.8, 45.88, 76.6 6],, and nd 663.3 3.33 (4 (44 4.55, 5, 777.9], 7 9], and 7. and 6M MWT m edia ed iann ia distance, 285 [189, 373], [201, 383], [226, 373] meters baseline, di dist stan st ance an c , 28 ce 85 [1 [18 89, 37 89, 73] 3],, 28 2284 4 [2 201 01,, 38 383] 3 , an 3] and 30 3088 [2 2266, 37 373 3] m eterrs att ba ase seli line li ne,, 12 aand ne ndd 224 4 respectively. weeks, respe pect ctiv ct iv velly. Echocardiographic measures At 24 weeks, there was no significant difference in changes in LV volumes, mass or ejection fraction between the allopurinol and placebo-treated patients (Table 2). For the entire cohort, there was little change in these measures over the study period (e.g., LVEF median, 26 [20, 33] % and 28 [21, 35] % at baseline and 24 weeks, respectively). Biomarkers Serum UA levels decreased significantly with allopurinol compared to placebo (Figure 2B, Table 3). Treatment differences (95% CI) were -4.2 (-4.9, -3.5) mg/dL and -3.5 (-4.2, -2.7)

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mg/dL at 12 and 24 weeks, respectively (both P

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study.

Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes...
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