HomeCirculation: Heart FailureVol. 3, No. 3Response to Letter Regarding Article, “Uric Acid-Lowering Treatment With Benzbromarone in Patients With Heart Failure: A Double-Blind Placebo-Controlled Cross-Over Preliminary Study” Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Letter Regarding Article, “Uric Acid-Lowering Treatment With Benzbromarone in Patients With Heart Failure: A Double-Blind Placebo-Controlled Cross-Over Preliminary Study” Wolfram Doehner, Stefan D. Anker and Kazuhide Ogino Wolfram DoehnerWolfram Doehner Search for more papers by this author , Stefan D. AnkerStefan D. Anker Search for more papers by this author and Kazuhide OginoKazuhide Ogino Search for more papers by this author Originally published1 May 2010https://doi.org/10.1161/CIRCHEARTFAILURE.110.953901Circulation: Heart Failure. 2010;3:e14Response:The points raised by George are important issues in the ongoing discussion of the role of uric acid in the cardiovascular disease setting.First, evidence is accumulating that uric acid (UA) lowering without inhibition of xanthine oxidase seems ineffective to prevent detrimental effects seen in hyperuricemic patients. In fact, 3 different approaches to directly lower uric acid levels have recently been tested using the renal reabsorption inhibitors benzbromarone1 and probenecid2 to increase UA excretion or the enzyme urate oxidase to promote the further degradation of uric acid to allantoin.3 Reduction of UA levels by these therapies was 34%, 46%, and 64%, which levels and even exceeds the UA-lowering effect of allopurinol in these patients.4 All 3 compounds failed, however, to improve endothelium function of other measures of clinical status that, in turn, has repeatedly been observed after therapy with xanthine oxidase inhibitors. The combined conclusion from these studies therefore seems fairly solid that xanthine oxidase rather than UA may be the true target in this therapeutic approach. These data do not exclude any role of uric acid itself in this context, and we fully agree with George, that the multiple and in parts conflicting interactions of UA are complex and difficult to untangle.In our study, we did not aim to assess the effect specifically on endothelial function and oxygen radical turn-over, both of which has been tested before in a number of studies. Assuming the multiple effects of increased reactive oxygen species accumulation by upregulated xanthine oxidase activity, the aim of our study was to assess the interaction with glucose metabolic pathways, inflammatory mediators, and disease markers of chronic heart failure (CHF). We could confirm the role of UA as a marker of disease severity in CHF without being itself a predominant pathophysiologic regulator because lowering of UA by benzbromarone did not translate into clinical benefits.Finally, George points out that beneficial effects of allopurinol on vascular function were observed in normouricemic patients, rendering UA obsolete as indicator of patients at risk. It should be noted, however, that mean UA levels of the discussed patient cohorts were well above the upper limit of normal. Whether the effects of allopurinol seen in these studies were mainly driven by hyperuricemic patients or were similar in all patients cannot be said. In turn, comparing the results from studies in patients with normal and with increased UA levels, a remarkable difference was observed because effects were exclusively present in hyperuricemic patients and not present on patients with normal UA levels.5 A further counterargument emerged from the results of the OPT-CHF trial.6 In this study, no clinical effect has been observed by xanthine oxidase inhibition in the overall study population that, notably, had been enrolled without screening for UA levels. Only a post hoc subgroup analysis in patients with increased UA levels suggested that benefits occur in hyperuricemic patients in a manner correlating with the degree of UA reduction. We therefore believe that increased UA levels are an important indicator to identify patients who may benefit from this tailored therapy.A further aspect in this discussion emerges as to the best cut-off for UA to identify patients at risk. UA has been demonstrated as powerful prognostic marker in patients with CHF independent of other established prognosticators in CHF.7 In these studies, ROC analyses identified the best UA level for predicting survival status at 12 or 18 months to be 565 μmol/L (9.50 mg/dL). The prognostic and symptomatic implications combined with the affordable and ubiquitous availability of UA assessment suggest to add UA to the routine assessments in CHF.DisclosuresNone.