***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: BACKGROUND The prognostic impact of hyperuricemia on long-term clinical outcomes in patients with chronic heart failure ( HF ) has been investigated in observational registries and clinical trials , but the results have been often inconclusive . We examined the prognostic impact of elevated serum uric acid levels on long-term clinical outcomes in the GISSI-HF ( Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure ) trial . CLINICAL TRIAL REGISTRATION CLINICAL TRIALS . GOV IDENTIFIER NCT00336336 . METHODS We assessed the rates of all-cause death , cardiovascular death , cardiovascular hospitalization and the composite of all-cause death or cardiovascular hospitalization over a median follow-up of 3.9 years among 6683 ambulatory patients with chronic HF . RESULTS Patients in the 3rd serum uric acid tertile ( > 7.2 mg/dl ) had a nearly 1.8-fold increased risk of both all-cause death and cardiovascular death , and a nearly 1.5-fold increased risk of cardiovascular hospitalization and of the composite endpoint compared to those in the 1st uric acid tertile ( < 5.7 mg/dl ) . Beyond serum uric acid ≥ 7 mg/dl the risk of outcomes increased sharply and linearly . The significant association between elevated serum uric acid levels and adverse outcomes persisted after adjustment for multiple established cardiovascular risk factors , HF etiology , left ventricular ejection fraction , medication use and other potential confounders , with an adjusted hazard ratio of 1.37 ( 95 % CI 1.22 - 1.55 ) for all-cause death , 1.48 ( 1.29 - 1.69 ) for cardiovascular death , 1.19 ( 1.09 - 1.30 ) for cardiovascular hospitalization and 1.21 ( 1.11 - 1.31 ) for the composite endpoint , respectively . CONCLUSIONS Elevated serum uric acid levels are independently associated with poor long-term survival and increased risk of cardiovascular hospitalization in patients with chronic HF Background — Oxidative stress may contribute to heart failure ( HF ) progression . Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes . Methods and Results — We r and omly assigned 253 patients with symptomatic HF , left ventricular ejection fraction ⩽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 end point at 24 weeks was based on survival , worsening HF , and patient global assessment . Secondary end points included change in quality of life , submaximal exercise capacity , and left ventricular ejection fraction . Uric acid levels were significantly reduced with allopurinol in comparison with placebo ( treatment difference , –4.2 [ –4.9 , –3.5 ] mg/dL and –3.5 [ –4.2 , –2.7 ] mg/dL at 12 and 24 weeks , respectively , both P<0.0001 ) . At 24 weeks , there was no significant difference in clinical status between the allopurinol- and placebo-treated patients ( worsened 45 % versus 46 % , unchanged 42 % versus 34 % , improved 13 % versus 19 % , respectively ; P=0.68 ) . At 12 and 24 weeks , there was no significant difference in change in Kansas City Cardiomyopathy Question naire scores or 6-minute walk distances between the 2 groups . At 24 weeks , left ventricular ejection fraction did not change in either group or between groups . Rash occurred more frequently with allopurinol ( 10 % versus 2 % , P=0.01 ) , but there was no difference in serious adverse event rates between the groups ( 20 % versus 15 % , P=0.36 ) . Conclusions — In high-risk HF patients with reduced ejection fraction and elevated uric acid levels , xanthine oxidase inhibition with allopurinol failed to improve clinical status , exercise capacity , quality of life , or left ventricular ejection fraction at 24 weeks . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00987415 Background and Aim : Increased xanthine oxidase ( XO ) activity may contribute to heart failure pathophysiology . This study evaluated whether a XO inhibitor , allopurinol produces clinical and functional benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy as estimated by global left myocardial function . Patients and Methods : Fifty-nine patients with a diagnosis of chronic heart failure due to coronary heart disease or idiopathic dilated cardiomyopathy and 20 healthy controls who attended the outpatient clinic of cardiology were subjected to full echocardiographic study including left ventricular diastolic and systolic function , and the combined index of myocardial performance [ Tei index : isovolumetric relaxation time ( IRT ) + isovolumetric contraction time (ICT)/ejection time ( ET ) ] . Patients were r and omized to allopurinol ( 300 mg/day ) or placebo . Improvement at 36 weeks was assessed using a composite end point comprising global left cardiac function as well as heart failure morbidity and mortality . Results : The percentage of patients characterized as improved , unchanged , or worsened did not differ between those receiving allopurinol or placebo . Allopurinol reduced serum uric acid ( SUA ) by 1.5 mg/dL ( P = 0.001 ) . In a subgroup analysis , patients with elevated SUA ( more than 7mg/ dL ) responded favorably to allopurinol whereas those with SUA less than 7mg/dL exhibited a trend toward no change . In addition , SUA reduction to allopurinol correlated with favorable clinical and functional response . Within the entire allopurinol patient cohort , those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who did not change ( P = 0.0007 ) . In placebo patients , lower baseline SUA , but not change in SUA , correlated with improved clinical outcome . Conclusions : Allopurinol did not produce significant clinical and functional improvement in unselected patients with moderate-to-severe heart failure . However , it is suggested that it is useful in patients with elevated SUA in a manner according to degree of SUA reduction . SUA may serve as a valuable biomarker to target heart failure therapy Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Introduction : Allopurinol used in the treatment of gout has been shown to improve the vascular endothelial dysfunction and reduce the dysfunction of the failing heart . This study was done to evaluate the effect and safety of allopurinol in non-hyperuricemic patients with chronic severe left ventricular ( LV ) dysfunction . Methods : In this study , 35 consecutive cases of non-hyperuricemic patients with chronic heart failure who had severe LV systolic dysfunction ( ejection fraction of less than 35 % ) and were on optimal guideline directed medical therapies for at least 3 months were included .  Allopurinol was administered with the dose of 300 mg po daily for 1 week and then it was up-titrated to a dose of 600 mg po daily for 3 months . Six minute walk test , strain imaging , laboratory testing  were done for every patient at baseline and after 3 months treatment with allopurinol . Results : In this study 30 heart failure ( HF ) patients with a mean age of 49.3 ± 14.4 years old were evaluated . No adverse effects were reported except for one case of skin rash after 4 days treatment which was excluded from the study . Study showed significant improvement of six minute walk test of the patients from 384.5 ± 81.5 meters to 402.8 ± 89.6 meters and the global longitudinal peak strain ( P < 0.001 ) . There was also significant decrease in the level of erythrocyte sedimentation rate and N-terminal pro-brain natriuretic peptide ( NT-proBNP ) after 3 months . Conclusion : Allopurinol could be of benefit in non-hyperuricemic patients with severe LV systolic dysfunction without significant adverse effects . R and omized clinical trials are needed in future to confirm the results BACKGROUND Reactive oxygen species ( ROS ) have been linked to hypertrophy , remodeling and abnormal excitation-contraction coupling . Previous data demonstrated that an increase in oxidative stress is associated to the pathogenesis of congestive heart failure ( CHF ) . We examined whether inhibition of the superoxide anion ( * O2(-))-generating enzyme xanthine oxidase ( XO ) with oxypurinol may improve cardiac function in patients with CHF . METHODS AND RESULTS A r and omized , placebo-controlled , double-blind study on 60 patients ( 30/group ) with New York Heart Association class II-III CHF , comparing 600-mg/day oxypurinol during 1 month with placebo , added to st and ard therapy . Effects on left ventricular ejection fraction ( LVEF ) , serum uric acid ( SUA ) level , and 6-minute walking test were analyzed . SUA decreased by 16.0 + /- 2.8 mg/L from baseline to Week 4 in the oxypurinol group relative to placebo ( P < .01 , n = 30 per group ) . LVEF showed an increase of 4.7 + /- 2.6 % from baseline to Week 4 in the oxypurinol group relative to placebo that did not reach statistical significance ( P < .08 ) . When patients with LVEF > 40 % at baseline were excluded , a statistically significant increase of 6.8 + /- 2.8 % from baseline to Week 4 was seen in the oxypurinol group relative to placebo ( P < .02 , n = 26 placebo , n = 21 oxypurinol ) . No treatment-related adverse effects or increase in walking capacity were detected . CONCLUSION Inhibition of XO by oxypurinol in patients with CHF decreases SUA and improves LVEF in patients with LVEF < or = 40 % after 1 month of treatment BACKGROUND Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure ( HF ) in relation to xanthine oxidase inhibitor therapy . METHODS The Prospect i ve R and omized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction < 30 % . For analysis , the population was divided into  uric acid quartiles among nonallopurinol users ( 2.2 - 7.1 , > 7.1 - 8.6 , > 8.6 - 10.4 , > 10.4 mg/dL ) and those using allopurinol . Multivariate Cox regression modeling was performed to identify predictors of mortality .  Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile . RESULTS A total of 1,152 patients were included . In general , patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF , including worse renal function and greater proportion of New York Heart Association class IV patients , and greater diuretic use . The allopurinol group and highest uric acid quartile had the highest total mortality ( 41.7 and 42.4 per 100 person-years , respectively ) and combined morbidity/mortality ( 45.6 and 51.0 per 100 person-years , respectively ) . Allopurinol use and highest uric acid quartile were independently associated with mortality ( hazard ratio [ HR ] 1.65 , 95 % CI 1.22 - 2.23 , P = .001 and HR 1.35 , 95 % CI 1.07 - 1.72 , P = .01 , respectively ) and combined morbidity/mortality ( uric acid quartile 4 vs 1 : HR 1.32 , 95 % CI 1.06 - 1.66 , P = .02 ; allopurinol use : HR 1.48 , 95 % CI 1.11 - 1.99 , P = .008 ) . CONCLUSION Elevated uric acid level was independently associated with mortality in patients with severe systolic HF , even when accounting for allopurinol use Several reports suggest that markers of renal function such as serum creatinine , serum uric acid , and urinary excretion of protein may be related to cardiovascular complications and mortality . This study analyzed the data from the Syst-Eur trial , which was a r and omized , placebo-controlled , double-blind intervention trial in elderly patients with isolated systolic hypertension . The purpose was to evaluate whether serum levels of creatinine and uric acid and urinary protein excretion at entry are related to subsequent morbid 
    Output:
    
Uric acid-lowering treatments  increase all-cause and CV mortality but did not increase CV hospitalization significantly in this study