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Impact of Serum Uric Acid Lowering and Contemporary Uric Acid-Lowering Therapies on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

ABSTRACT: Objective: This study aimed to evaluate the potential association between uric acid (UA) lowering and cardiovascular risk reduction among UA-lowering therapies in adults. Methods: A systematic search for randomized controlled trials (RCTs) was conducted according to the protocol pre-registered in PROSPERO (No. CRD42020199259). We search for RCTs in PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov up to July 1, 2020. A meta-analysis was performed using a fixed- or random-effects model. Results: In total, 30 studies involving 18,585 hyperuricaemic patients were included. Xanthine oxidase inhibitor (XOI) therapy produced a 6.0% reduction in relative risk (RR) for major adverse cardiovascular events (MACEs). The use of febuxostat was associated with a higher risk of cardiovascular events (CVEs) (RR: 1.09, 95% CI 0.998-1.19, I ² = 0.0%), but the difference was not statistically significant. Allopurinol treatment was associated with a lower CVE risk (RR: 0.61, 95% CI 0.46-0.80, I ² = 21.0%). Among the UA-lowering therapies, the drug treatments were associated with all-cause mortality (RR: 1.20, 95% CI 1.02-1.41, I ² = 0.0%). The subgroup with a UA endpoint <7 mg/dl was not associated with a higher CVE risk (RR: 0.57, 95% CI 0.35-0.92, I ² = 0.0%), and in the subgroup with a UA endpoint <5 mg/dl group, a lower risk of CVEs was not observed (RR: 0.99, 95% CI 0.69-1.44, I ² = 0.0%). Conclusions: UA reduction caused by XOIs reduced the incidence of MACEs. UA-lowering medicines were associated with changes in all-cause mortality but not cardiovascular outcomes. The lower UA endpoint was not associated with reduced cardiovascular risk.

SUBMITTER: Ying H

PROVIDER: S-EPMC8044896 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied (n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.

Project description:IntroductionHyperuricaemia has been implicated in the development of kidney function in populations with chronic kidney disease; however, the benefits of urate-lowering therapy (ULT) remain uncertain in different clinical studies. The different kidney functions of enrolled populations and distinct pharmacokinetic characteristics of ULT might be of the essence for the contrasting results. In this study, we will synthesise all available data from randomised controlled trials (RCTs) and cohort studies, then evaluate the outcomes of ULT in patients stratified by different estimated glomerular filtration rate (eGFR) stratifications. Furthermore, we will attempt to explore a relatively optimal ULT regimen using a Bayesian network meta-analysis in different eGFRs.Methods and analysisWe searched published and unpublished data from MEDLINE, EMBASE, the Cochrane Central Register of Controlled trials and ClinicalTrials.gov website (before March 2022) for RCTs and cohort studies without language restriction. In the pairwise meta-analysis, all regimens of ULT will be pooled as a whole and compared with controls in different eGFRs. The random-effects model will be applied to generate the summary values using the software Stata V.12.0 (StataCorp). Network meta-analysis within a Bayesian framework will be conducted to explore the relative efficacy profiles of different ULTs and to find optimal ULT in different eGFRs. The software of WinBUGS V.1.4.3 and R2WinBUGS package of R V.3.1.1 will be used in the network meta-analysis. Primary outcomes will be the occurrence of major cardiovascular events and kidney failure events. Secondary outcomes will include the rate of change in eGFR per year, all-cause death, changes in serum uric acid level and major adverse events. Two authors will independently review study selection, data extraction and quality assessment.Ethics and disseminationThe meta-analysis does not require ethical certification. The results will be disseminated through publication in a peer-reviewed journal and through presentations at academic conferences.Prospero registration numberCRD42021226163.

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Impact of Serum Uric Acid Lowering and Contemporary Uric Acid-Lowering Therapies on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

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