| Objective:We will conduct a systematic review,Meta-analysis and network Meta-analysis of randomized controlled trials and cohort studies to find the answer to the effect of uric acid lowering therapy on renal and cardiovascular events.Traditional Meta-analysis will summarize renal outcomes and cardiovascular events.Bayesian network Meta-analysis will be used to explore whether there are optimal therapeutic drugs for patients with different renal functions.Methods:We will search for published,unpublished and ongoing studies in a range of research registries.Searches for published RCTs and cohort studies will be undertaken in the following databases from the inception of databases to 1 March 2022:EMBASE,Ovid MEDLINE and Cochrane Central Register of Controlled trials to find all relevant randomised controlled trials and observational studies with every language.In the traditional meta-analysis,all uric acid-lowering therapy(ULT)will be combined as a whole and compared with conventional treatment or placebo.Traditional Meta analysis of the relevant data was performed using Stata12.0(Stata Corp).The network meta-analysis will be conducted in a Bayesian framework to explore the relative efficacy profiles of different ULT and to find the best therapy.The network meta-analysis will use the R2Win BUGS package of Win BUGS1.4.3 software and Rsoftware3.1.1.The primary outcome was the occurrence of major cardiovascular events and kidney failure events.Kidney failure events were defined as including e GFR decrease of more than 25%or 50%and doubling of serum creatinine levels or reaching end-stage renal disease(end-stage renal disease was defined as e GFR<15m L/min/1.73m~2or initiation of renal replacement therapy).Major cardiovascular events include cardiovascular death,non-fatal myocardial infarction,non-fatal stroke,heart failure requiring hospitalization,and unstable angina requiring emergency coronary revascularization.Secondary outcomes included the rate of change in estimated glomerularfilt rationrate(e GFR)per year,all-cause death,change in serum uric acid level from baseline to end of follow-up and major adverse events.Quality of evidence will be sent to you by GRADE(Grading of Recommendations Assessment Development and Evaluation)software and CINe MA(Confidence in Network Mate-analysis),network application.Results:A total of 65 studies were included in this study,including 247,300 subjects.The results showed that for the whole population,uric acid-lowering therapy could significantly reduce the occurrence of kidney failure events(RR=0.69,95%CI0.48-0.99,P<0.05),but there was no significant difference in the incidence of cardiovascular events between ULT and non-uric-lowering therapy(RR=0.78,95%CI 0.57～1.070,P<0.05,I~2=98.6%).In terms of the rate of e GFR change,it was significantly decreased and the progression of kidney function was delayed(WMD=3.126,95%CI 1.083-5.169,P<0.05,I~2=95.6%)in the ULT group.For all-cause deaths,uric acid-lowering therapy resulted in a significant 30%reduction compared with no ULT(RR=0.70,95%CI 0.50-0.99,I~2=87.5%).For change in serum uric acid level,the head-to-head study of febuxostat VS.allopurinol showed that febuxostat was superior to allopurinol(WMD=1.436,95%CI0.839-2.088,P<0.05,I~2=96.9%).Bayesian network meta-analysis showed that febuxostat was superior to other ULT in cardiovascular outcomes,including benzromarone,probenecid,allopurinol and oxypurinol.In kidney outcome events,all-cause death and the rate of change in e GFR per year,there was no significant difference in the efficacy of different uric acid-lowering treatments.A total of 3,414 subjects were enrolled in 20 studies in patients with e GFR 15-60ml/min/1.73m~2.Compared with no ULT,ULT significantly reduced the incidence of kidney outcome events by 40%(RR=0.60,95%CI 0.41-0.91,P<0.05).For major cardiovascular events and all-cause deaths,ULT did not significantly reduce the incidence compared with no uric acid-lowering therapy(major cardiovascular events:RR=0.74,95%CI 0.51-1.07,P=0.304,I~2=17.4%;All-cause death:RR=0.925,95%CI 0.592～1.447,I~2=0%,P=0.416).Network meta-analysis showed that there was no significant difference in the efficacy of different kinds of uric acid-lowering treatments on the above outcome events in people with e GFR 15-60ml/min/1.73m~2.Conclusion:For the entire population,ULT significantly reduced the risk of kidney outcome events and the rate of e GFR change,and also benefited from all-cause mortality.However,ULT and non-ULT had no significant effect on the outcome of cardiovascular events.In patients with e GFR15-60ml/min/1.73m~2,ULT significantly reduced the risk of renal outcome events,but did not reduce the rate of e GFR change or mortality or cardiovascular events.Regarding the differences among different uric acid-lowering agents,febuxostat may be superior to other ULT in the outcome of cardiovascular events. |
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