Secondary Prevention Of Major Cerebrovascular Events With Seven Different Statins:Systematic Review And Network Meta-analysis

Background:On the basis of findings from randomized controlled trials(RCTs),statins have been a major strategy in reducing the risk for atherosclerotic cardiovascular diseases(ASCVD).Several clinical trials have shown that statins can significantly reduce serum LDL-C and effectively decrease the risk for stroke.Statins can reduce the incidence of major cardiovascular events,and thus,they have been recommended for the secondary prevention of ischemic stroke.Statins have been recommended for the use in ASCVD but different statins have distinct pharmacological characteristics.Objectives:This multi-treatment meta-analysis aimed to evaluate the efficacy of seven statins in the secondary prevention of major cerebrovascular events(CVEs).Methods and analyses:The PubMed,Embase,Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched to identify studies published between January 1,2011,and June 30,2016.We identified the studies prior to January 2011 from the bibliography of previously published systematic literature reviews and meta-analyses.The included randomized controlled trials investigated the efficacy of lovastatin,atorvastatin,fluvastatin,simvastatin,pitavastatin,pravastatin or rosuvastatin in the secondary prevention of CVEs.The primary outcomes were CVEs;the secondary outcomes were all-cause death,fatal stroke and nonfatal stroke.Meta-analysis and network meta-analysis were used for data synthesis.Results:A total of 42 studies with 82,601 patients were included for analysis.In the secondary prevention of ASCVD,the major CVEs in pravastatin(risk ratio[RR]0.87,0.76-0.99)-and atorvastatin(RR 0.59,0.49-0.72)-treated patients reduced significantly compared with controls.Compared to controls,the all-cause death was reduced by 12%in statins-treated patients(RR 0.88,0.81-0.96).Indirect comparisons with network meta-analysis showed that RR was 1.70(1.10-2.50)for atorvastatin compared with rosuvastatin.Indirect comparisons with network analysis showed a significant difference in the all-cause death between lovastatin and fluvastatin(3.60,1.10-14.00)and the nonfatal stroke between atorvastatin-treated patients and simvastatin-treated patients(RR1.90,1.10-3.70).Conclusion:Different statins have distinct pharmacological characteristics,and there are differences in statistical and clinical outcomes among several statins.Section1 Correlation between bilirubin and ischemic stroke:A systemic review and meta-analysis of observational evidenceStroke related death accounts for 1/3 world wide.Of more important,stroke has been the leading cause of death in China in recent years.Although much progress has been made in identifying risk factors for stroke,little is known about factors that modulate stroke risk.Serum bilirubin is a normal metabolite of heme.Traditionally,bilirubin is regarded as a toxic metabolite.In clinical practice,serum bilirubin has been used a marker of liver and hematopoietic diseases.In recent years,a variety of studies indicate that bilirubin may exert anti-oxidative,anti-inflammatory and neuroprotective effects.Some studies reveal that serum total bilirubin is negatively related to the risk for ischemic stroke.However,there is still controversy on this issue.Just case-control studies were included in previous Meta-analysis,or ischemic stroke wasnot the endpoint criteria.Objectives:Serum total bilirubin is a biomarker of ischemic stroke and may serve as a potential prognostic factor.It is imperative to systemically evaluate the correlation between serum total bilirubin and risk for stroke.Methods:Relevant studies published before 30 June 2017 were searched in four databases(PubMed,EMBASE,Web of Science and Cochrane Central).Additional studies were searched by reviewing references and contacting authors.Cohort,cross-sectional and case-control studies in adults that examined the association between serum bilirubin and stroke were included irrespective of language and date of publication.Abstract and full-text were reviewed by two independent reviewers,and disagreement was resolved by consulting a third reviewer.Data were extracted by two independent reviewers using a pre-designed data collection form.Odds ratio(OR)with corresponding 95%confidence interval(CI)was used for the evaluation of the relationship between bilirubin levels and stroke.The I2 statistic and x2 test were employed to assess the variability across studies attributable to heterogeneity beyond chance.A pooled effect was calculated with a fixed-effects model when there was no statistically significant heterogeneity;otherwise,a random effects model was employed.Subgroup was used to determine the robustness across different groups.Publication bias was evaluated by Egger test and funnel plot.Trim and fill method was used for adjustment once bias was present.Results:11 observational studies(5 prospective and 6 cross-sectional studies)involving 131450 subjects were included for analysis.In 4 studies with 83380 subjects,the relationship between bilirubin and ischemic stroke was investigated,ischemic stroke was found in 2496 patients,and the total OR of the highest bilirubin and the lowest bilirubin for the occurrence of ischemic stroke was 0.66(95%CI:0.58-0.74).11 studies with 131450 subjects explored the correlation between bilirubin and stroke,5060 cases of cerebral stroke were reported,and the total OR of the highest bilirubin and the lowest bilirubin for the occurrence of stroke was 0.73(95%CI:0.68-0.79).Conclusion:The available studies support an inverse association between bilirubin and risk for ischemic stroke and stroke.Large-scale prospective studies are needed to establish whether serum bilirubin can be used in the prevention of stroke.Section 2 Association of total bilirubin with diabetes mellitus in Chinese elderlyDisease spectrum has significantly changed in past 100 years,and noncommunicable diseases(NCD)including diabetes mellitus(DM),cancer and cardiovascular diseases have become the major cause of death world wide.DM has been one of the most important NCD and threatens the human health world wide.Oxidative stress plays important roles in the occurrence and development of DM.A variety of studies have shown that glucose overload may induce oxidative stress,causing damage to cells.However,the clinical intervention with vitamin E,a widely accepted anti-oxidant,fails to achieve favorable efficacy in DM patients.Bilirubin is an end product in the metabolism of heme and has been confirm to possess potential anti-oxidative activity and be negatively related to oxidative stress.Although bilirubin at a high level is toxic to nervous system,a large number of studies have revealed that bilirubin at appropriate elevated level is beneficial.The incidence of DM increases over age,however,the age-span is larger than 20 years or middle-aged/old people are recruited in available studies on the relationship between bilirubin and DM.Objectives:Serum total bilirubin(TB)was used as a predictor of diabetes mellitus(DM)and this study was undertaken to investigate the relationship between serum TB and DM.Methods:In this cross-sectional study,a total of 3867 subjects older than 65 years were recruited from East China.The anthropometric data,life style and past history were collected.The fasting blood glucose(FBG),total cholesterol,triglycerides,total bilirubin and alanine aminotransferase were detected.The prevalence of DM was calculated according to the serum TB quartiles.Logistic regression analysis was employed to evaluate the relationship between serum TB and DM.Results:It showed serum TB was negatively related to the prevalence of DM(P=0.032).Logistic regression analysis revealed that serum TB was an independent prognostic factor of DM(OR:0.944,95%CI:0.915-0.974).Conclusions:Our results showed serum TB in physiological range is an independent risk factor of DM in old people;prevalence of DM in old people has a linear relationship with serum TB quartiles;the prevalence of DM reduces with the increase in physiological serum TB.