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CLINICAL RESEARCH: CLINICAL TRIALS

Impact of Oxypurinol in Patients With Symptomatic Heart Failure

Results of the OPT-CHF Study

Joshua M. Hare, MD^_*,_*, Brian Mangal, MSc, Joanne Brown, BSc, Charles Fisher, Jr, MD, Ronald Freudenberger, MD, Wilson S. Colucci, MD, Douglas L. Mann, MD^||, Peter Liu, MD^¶, Michael M. Givertz, MD^#, Richard P. Schwarz, PhD^_* for the OPT-CHF Investigators

^_* The University of Miami Miller School of Medicine, Miami, Florida
Cardiome Pharma Corporation, Vancouver, British Columbia, Canada
Robert Wood Johnson University Hospital, New Brunswick, New Jersey
Boston University, Boston, Massachusetts
^|| Baylor Heart Clinic, Houston, Texas
^¶ Toronto General Hospital, Toronto, Ontario, Canada
^# Brigham & Women's Hospital, Boston, Massachusetts.

Manuscript received October 4, 2007; revised manuscript received January 2, 2008, accepted January 15, 2008.

^_* Reprint requests and correspondence: Dr. Joshua M. Hare, Division of Cardiology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1124, Miami, Florida 33136. (Email: jhare{at}med.miami.edu).

Objectives: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy.

Background: Increased XO activity may contribute to heart failure pathophysiology.

Methods: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life.

Results: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (–2.3 ± 2.1 mg/dl vs. –1.0 ± 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome.

Conclusions: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687 [ClinicalTrials.gov] )

Abbreviations and Acronyms   BNP = brain natriuretic peptide   CCE = composite clinical end point   CI = confidence interval   CV = cardiovascular   ITT = intent to treat   MLHF = Minnesota Living with Heart Failure   NYHA = New York Heart Association   PGHFCS = Patient Global Heart Failure Clinical Status   SUA = serum uric acid   XO = xanthine oxidase

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