Impact of oxypurinol in patients with symptomatic heart failure

被引:311
作者
Hare, Joshua M. [1 ]
Mangal, Brian [2 ]
Brown, Joanne [2 ]
Fisher, Charles, Jr. [2 ]
Freudenberger, Ronald [3 ]
Colucci, Wilson S. [4 ]
Mann, Douglas L. [5 ]
Liu, Peter [6 ]
Givertz, Michael M. [7 ]
Schwarz, Richard P. [1 ]
机构
[1] Univ Miami, Miller Sch Med, Div Cardiol, Miami, FL 33136 USA
[2] Cardiome Pharma Corp, Vancouver, BC, Canada
[3] Robert Wood Johnson Univ Hosp, New Brunswick, NJ USA
[4] Boston Univ, Boston, MA 02215 USA
[5] Baylor Heart Clin, Houston, TX USA
[6] Toronto Gen Hosp, Toronto, ON, Canada
[7] Brigham & Womens Hosp, Boston, MA 02115 USA
关键词
D O I
10.1016/j.jacc.2008.01.068
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 similar to 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).
引用
收藏
页码:2301 / 2309
页数:9
相关论文
共 25 条
[1]   Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure [J].
Amado, LC ;
Saliaris, AP ;
Raju, SVY ;
Lehrke, S ;
John, MS ;
Xie, JS ;
Stewart, G ;
Fitton, T ;
Minhas, KM ;
Brawn, J ;
Hare, JM .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2005, 39 (03) :531-536
[2]   Uric acid and survival in chronic heart failure - Validation and application in metabolic, functional, and Hemodynamic staging [J].
Anker, SD ;
Doehner, W ;
Rauchhaus, M ;
Sharma, R ;
Francis, D ;
Knosalla, C ;
Davos, CH ;
Cicoira, M ;
Shamim, W ;
Kemp, M ;
Segal, R ;
Osterziel, KJ ;
Leyva, F ;
Hetzer, R ;
Ponikowski, P ;
Coats, AJS .
CIRCULATION, 2003, 107 (15) :1991-1997
[3]   Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease [J].
Baldus, S ;
Köster, R ;
Chumley, P ;
Heitzer, T ;
Rudolph, V ;
Ostad, MA ;
Warnholtz, A ;
Staude, HJ ;
Thuneke, F ;
Koss, K ;
Berger, J ;
Meinertz, T ;
Freeman, BA ;
Münzel, T .
FREE RADICAL BIOLOGY AND MEDICINE, 2005, 39 (09) :1184-1190
[4]   Xanthine oxicloreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications [J].
Berry, CE ;
Hare, JM .
JOURNAL OF PHYSIOLOGY-LONDON, 2004, 555 (03) :589-606
[5]   Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy [J].
Cappola, TP ;
Kass, DA ;
Nelson, GS ;
Berger, RD ;
Rosas, GO ;
Kobeissi, ZA ;
Marbán, E ;
Hare, JM .
CIRCULATION, 2001, 104 (20) :2407-2411
[6]   The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients:: La Plata study [J].
Cingolani, Horacio E. ;
Plastino, Juan A. ;
Escudero, Eduardo M. ;
Mangal, Brian ;
Brown, Joanne ;
Perez, Nestor G. .
JOURNAL OF CARDIAC FAILURE, 2006, 12 (07) :491-498
[7]   Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction [J].
Doerries, Carola ;
Grote, Karsten ;
Hilfiker-Kleiner, Denise ;
Luchtefeld, Maren ;
Schaefer, Arnd ;
Holland, Steven M. ;
Sorrentino, Sajoscha ;
Manes, Costantina ;
Schieffer, Bernhard ;
Drexler, Helmut ;
Landmesser, Ulf .
CIRCULATION RESEARCH, 2007, 100 (06) :894-903
[8]   Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction -: A new action for an old drug? [J].
Engberding, N ;
Spiekermann, S ;
Schaefer, A ;
Heineke, A ;
Wiencke, A ;
Müller, M ;
Fuchs, M ;
Hilfiker-Kleiner, D ;
Hornig, B ;
Drexler, H ;
Landmesser, U .
CIRCULATION, 2004, 110 (15) :2175-2179
[9]   Allopurinol improves endothelial dysfunction in chronic heart failure [J].
Farquharson, CA ;
Butler, R ;
Hill, A ;
Belch, JJF ;
Struthers, AD .
CIRCULATION, 2002, 106 (02) :221-226
[10]   Rationale, design and organisation of an efficacy and safety study of oxypurinol added to standard therapy in patients with NYHA class III-IV congestive heart failure [J].
Freudenberger, RS ;
Schwarz, RP ;
Brown, J ;
Moore, A ;
Mann, D ;
Givertz, MM ;
Colucci, WS ;
Hare, JM .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2004, 13 (11) :1509-1516