***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: WHAT IS KNOWN AND OBJECTIVE There are no clinical reports that have compared topiroxostat , a selective xanthine oxidase inhibitor , with allopurinol in serum urate-lowering efficacy . The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout . METHODS A phase 3 , multicentre , r and omized , double-blind , double-dummy , active-controlled , parallel-group study conducted in Japan . Patients who had inadequate serum urate levels ( a gout patient : serum urate level ≥416·4 μmol/L ; an asymptomatic hyperuricemic patient with specific complications ( urinary lithiasis , hypertension , hyperlipidemia and /or diabetes ) : serum urate level ≥475·8 μmol/L ; and an asymptomatic hyperuricemic patient with no specific complications : serum urate level ≥535·3 μmol/L ) were r and omized  to topiroxostat 120 mg/day or allopurinol 200 mg/day , with an equal allocation ratio , for 16 weeks . To prevent the onset of gouty arthritis by rapid serum urate reduction , these doses were increased in a stepwise manner . The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit . RESULTS AND DISCUSSION Overall , 206 patients were r and omly assigned to topiroxostat and allopurinol . Two hundred and three patients ( allopurinol : n = 105 , topiroxostat : n = 98 ) received at least one dose of the study drug and had their serum urate level assessed at least once . The baseline characteristics were comparable between groups . The mean age of patients was 53·0 ± 11·4 years and 99 % of patients were male .  The primary efficacy endpoint was -34·3 ± 11·1 % in the allopurinol group ( n = 105 ) and -36·3 ± 12·7 % in the topiroxostat group ( n = 98 ) . Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin ( 95 % confidence interval , -5·3 to 1·3 % ) . The overall incidences of adverse events and adverse drug reactions were similar between both groups . WHAT IS NEW AND CONCLUSION Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12‐month phase III trial in patients with tophaceous gout To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout ( 1 or 2 gout flares ) Objectives To assess the efficacy and tolerability of lesinurad , an oral selective uric acid reabsorption inhibitor , in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol . Methods Patients ( N=227 ) with an inadequate response to allopurinol , defined as serum urate ( sUA ) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol , were r and omised 2:1 to 4 weeks of double-blind treatment with lesinurad ( 200 , 400 or 600 mg/day ) or matching placebo in combination with their pre study allopurinol dose ( 200–600 mg/day ) . Colchicine prophylaxis for gout flares was required . The primary end point was percent reduction from baseline sUA levels at 4 weeks . A pharmacokinetic sub study was also conducted . Safety was assessed throughout . Results Patients ( n=208 ) received ≥1 dose of blinded medication . Lesinurad 200 , 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16 % , 22 % and 30 % , respectively , versus a mean 3 % increase with placebo ( p<0.0001 , all doses vs placebo ) . Similar results were observed in patients with mild or moderate renal insufficiency ( estimated creatinine clearance 30 to < 90 mL/min ) . The incidence of ≥1 treatment-emergent adverse event was 46 % , 48 % and 54 % with lesinurad 200 , 400 and 600 mg , respectively , and 46 % with placebo ( most frequent , gout flares , arthralgia , headache and nasopharyngitis ) , with no deaths or serious adverse events . Conclusions Lesinurad achieves clinical ly relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone . Trial registration number NCT01001338 Background Urate-lowering therapy ( ULT ) is associated with low rates of adherence , leading to a potential risk of relapse of gouty arthritis , tophi , or urolithiasis . Our main aim was to identify the recurrence of gouty arthritis , tophi , or urolithiasis after discontinuation of ULT . Secondary aims included an assessment of ULT re introduction rates and factors associated with relapse . Methods We conducted a systematic literature review of clinical studies investigating the effect of discontinuing any ULT ( allopurinol , febuxostat , probenecid , sulfinpyrazone , benzbromarone ) in adults on long-term therapy . We search ed The Cochrane Central Register of Controlled Trials , MEDLINE , EMBASE , Science Citation Index , and Clinical Trials.gov from inception to March 2016 . Conference abstract s of the ACR/ARHP and EULAR annual conferences were h and - search ed . Study quality was assessed using the first eight items of the method ological index for non-r and omized studies ( MINORS ) tool . The review protocol is registered with PROSPERO ( CRD42016042048 ) . Results A total of 4640 articles were identified , eight of which were ultimately included . Most of these studies pre date d 2000 . MINORS scores ranged from 5 to 10 out of a possible 16 . Mean follow-up duration after discontinuation ranged from 12 to 96 months . Five studies focused on discontinuation of ULT in gouty arthritis and tophi , two in urolithiasis , and one in asymptomatic hyperuricemia . Relapse rates were high in gout ( 36—81 % ) and lower in urolithiasis ( 15 % ) . Relapses occurred 1–4.5 years after ULT discontinuation . In one study , a low serum urate level before and after ULT discontinuation was associated with lower gout recurrence . Discussion Relapse of gout is common although delayed after discontinuation of ULT . Short-term prognosis after ULT discontinuation appears favorable if the serum urate level was low before ULT discontinuation . The results of this review are limited by the paucity of existing studies and their low quality . Further comparative studies should consider larger primary care population s and discontinuation of febuxostat Objective To investigate the efficacy and safety of lesinurad , a selective uric acid reabsorption inhibitor , in a 6 month , phase 3 clinical trial and extension study . Methods Patients with gout who can not take a xanthine oxidase inhibitor ( XOI ) and have serum uric acid ( sUA ) ⩾6.5 mg/dl were r and omized to receive oral lesinurad ( 400 mg daily ) or placebo . The primary endpoint was the proportion of patients with sUA < 6.0 mg/dl at month 6 . Safety assessment s included treatment-emergent adverse events ( TEAEs ) and laboratory data . Patients who completed the study were eligible for an open-label , uncontrolled extension study of lesinurad 400 mg monotherapy . Results Patients ( n = 214 ) were primarily white males ( mean age 54.4 years ; gout duration 11.2 years ) . Significantly more patients achieved the primary endpoint with lesinurad than placebo ( 29.9 vs 1.9 % ; P < 0.0001 ) . Overall TEAE rates were higher with lesinurad ( 77.6 vs 65.4 % ) ; renal-related TEAEs ( 17.8 % ) , renal-related serious TEAEs ( 4.7 % ) and serum creatinine elevations ( 1.5 times baseline , 24.3 % ) occurred only with lesinurad . A total of 143 patients ( 65 lesinurad , 78 placebo ) enrolled in the extension study . Treatment with lesinurad 400 mg result ed in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely . No new safety findings were observed in the extension . Conclusion In patients with gout and intolerance/contraindication to XOIs , lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo , with sustained effects for up to 18 months . Due to a high incidence of serum creatinine elevations and renal-related adverse events , including serious adverse events with lesinurad 400 mg , lesinurad should not be used as monotherapy . Trial registration Clinical Trials.gov ( http://clinincaltrials.gov ) , NCT01508702 BACKGROUND Cardiovascular risk is increased in patients with gout . We compared cardiovascular outcomes associated with febuxostat , a nonpurine xanthine oxidase inhibitor , with those associated with allopurinol , a purine base analogue xanthine oxidase inhibitor , in patients with gout and cardiovascular disease . METHODS We conducted a multicenter , double‐blind , noninferiority trial involving patients with gout and cardiovascular disease ; patients were r and omly assigned to receive febuxostat or allopurinol and were stratified according to kidney function . The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point ( a composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , or unstable angina with urgent revascularization ) . RESULTS In total , 6190 patients underwent r and omization , received febuxostat or allopurinol , and were followed for a median of 32 months ( maximum , 85 months ) . The trial regimen was discontinued in 56.6 % of patients , and 45.0 % discontinued follow‐up . In the modified intention‐to‐treat analysis , a primary end‐point event occurred in 335 patients ( 10.8 % ) in the febuxostat group and in 321 patients ( 10.4 % ) in the allopurinol group ( hazard ratio , 1.03 ; upper limit of the one‐sided 98.5 % confidence interval [ CI ] , 1.23 ; P = 0.002 for noninferiority ) . All‐cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group ( hazard ratio for death from any cause , 1.22 [ 95 % CI , 1.01 to 1.47 ] ; hazard ratio for cardiovascular death , 1.34 [ 95 % CI , 1.03 to 1.73 ] ) . The results with regard to the primary end point and all‐cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention‐to‐treat analysis . CONCLUSIONS In patients with gout and major cardiovascular coexisting conditions , febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events . Allcause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol . ( Funded by Takeda Development Center Americas ; CARES Clinical Trials.gov number , NCT01101035 . AIMS Dual-urate-lowering therapy ( ULT ) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout . Uricosuric agents can cause hyperuricosuria , a risk factor for nephrolithiasis and acute uric acid nephropathy . The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy , and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs . METHODS The impact of poor medication adherence was studied using two-compartment pharmacokinetic ( PK ) models based on published evidence , and a semi-mechanistic four-compartment pharmacodynamic ( PD ) model . The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion ( lowered clearance ) or overproduction of uric acid , with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at r and om . RESULT 
    Output:
    
The new findings were as follows : ( i ) dual-agent ULTs were superior to febuxostat alone , and further surveillance on the adverse effects when lesinurad is uptitrated is needed , and ( ii ) terminalia bellerica 500 mg/day , a novel xanthine oxidase inhibitor ( XOI ) made of natural fruit extracts , and topiroxostat ≥ 80 mg/day , an XOI used mostly in Japan , could be new effective options for lowering the occurrence of adherence attrition events .
Key Points • Dual-agent ULTs were superior to febuxostat alone , and further surveillance on the adverse-effects when lesinurad is uptitrated is needed . •
Terminalia bellerica 500 mg/day , a novel xanthine oxidase inhibitor ( XOI ) made of natural fruit extracts , and topiroxostat 80 mg/day , an XOI used mostly in Japan , could be new effective options for lowering the occurrence of adherence attrition events .
Key Points • Dual-agent ULTs were superior to febuxostat alone , and further surveillance on the adverse-effects when lesinurad is uptitrated is needed . •
Terminalia bellerica 500 mg/day , a novel xanthine oxidase inhibitor ( XOI ) made of natural fruit extracts , and topiroxostat 80 mg/day , an XOI used mostly in Japan , could be new effective options for lowering the occurrence of adherence attrition events