| BackgroundCardiovascular disease(CVD)remains the leading cause of death worldwide,is an increasing cause of morbidity and a major cause of disability and ill?health.CVD produces immense health and economic burdens globally,therefore preventing deaths and diseases due to CVD is a priority for global public health.CVD is multi?factorial in its causation.One of the major modifiable risk factors for CVD is thought to be high levels of blood cholesterol,therefore lowering cholesterol,in particular low?density lipoprotein cholesterol(LDL?C),is considered an important target of therapy in the primary and secondary prevention of CVD.The use of statins is the preferred treatment strategy for the prevention of CVD,but some people at high?risk for CVD are intolerant to statin therapy or unable to achieve their treatment goals with the maximal recommended doses of statin.Therefore,the combination of non?statin lipid?modifying drugs with the lowest statin dose tolerated or,as an alternative,a combination of non?statin lipid?modifying drugs,represent possible approaches for these people.Ezetimibe is a non?statin lipid?modifying drug,which is the first and only selective inhibitor of intestinal cholesterol absorption.It is an effective LDL?C lowering agent,which is safe and well?tolerated.However,whether it has a positive effect on CVD events remains uncertain.Results from clinical studies are inconsistent and a thorough evaluation of its efficacy and safety for the prevention of CVD and mortality is necessary.ObjectivesTo assess the efficacy and safety of ezetimibe for the prevention of CVD and all?cause mortality.Search methodsWe searched the CENTRAL,MEDLINE,Embase and Web of Science on 27 June 2018,and also conducted a search of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform(ICTRP)Search Portal(apps.who.int/trialsearch/)for relevant RCTs on 11 July 2018.We checked reference lists from primary studies and review articles for additional studies.No language restrictions were applied.Selection criteriaWe included randomised controlled trials(RCTs)that compared ezetimibe versus placebo or ezetimibe plus other lipid?modifying drugs versus other lipid?modifying drugs alone in adults,with or without CVD,and which had a follow?up of at least 12 months.Cluster?RCTs,cross?over trials and observation studies were ineligible.Data collection and analysisTwo review authors independently selected studies for inclusion,extracted data and assessed risk of bias.Any disagreements were resolved by reaching consensus or by involving a third review author.Study authors were contacted to obtain additional information and missing outcome data where possible.We performed statistical analyses using RevMan 5.3 according to the Cochrane Handbook for Systematic Reviews of Interventions.We calculated risk ratios(RR)for dichotomous data and mean differences(MD)for continuous data with 95% confidence intervals(CI).We used chi-square test and I-square to assess the heterogeneity of included studies.We planned to perform subgroup analyses to investigate the heterogeneity.We conducted several sensitivity analyses to examin the stability of the results.We used the Grading of Recommendations,Assessment,Development and Evaluation(GRADE)approach to evaluate the quality of evidence.Main resultsWe included 26 RCTs randomising 23,499 participants.All included studies assessed effects of ezetimibe plus other lipid?modifying drugs compared with other lipid?modifying drugs alone or plus placebo.Our findings were driven by the largest study(IMPROVE?IT),which had weights ranging from 41.5% to 98.4% in the different meta?analyses.Ezetimibe with statins probably reduces the risk of major adverse cardiovascular events compared with statins alone(RR 0.94,95% CI 0.90 to 0.98;a decrease from 284/1000 to 267/1000 people,95% CI 256 to 278;21,727 participants;10 studies;moderate?quality evidence).Trials reporting all?cause mortality used ezetimibe with statin or fenofibrate and found they have little or no effect on this outcome(RR 0.98,95% CI 0.91 to 1.05;21,222 participants;8 studies;high?quality evidence).Adding ezetimibe to statins probably reduces the risk of non?fatal myocardial infarction(MI)(RR 0.88,95% CI 0.81 to 0.95;a decrease from 105/1000 to 92/1000 people,95% CI 85 to 100;21,145 participants;6 studies;moderate?quality evidence)and non?fatal stroke(RR 0.83,95% CI 0.71 to 0.97;a decrease 32/1000 to 27/1000 people,95% CI 23 to 31;21,205 participants;6 studies;moderate?quality evidence).Trials reporting cardiovascular mortality added ezetimibe to statin or fenofibrate,probably having little or no effect on this outcome(RR 1.00,95% CI 0.89 to 1.12;19457 participants;6 studies;moderate?quality evidence).The need for coronary revascularisation might be reduced by adding ezetimibe to statin(RR 0.94,95% CI 0.89 to 0.99;a decrease from 196/1000 to 184/1000,95% 17 5 to 194 people;21,323 participants;7 studies);however,no difference in coronary revascularisation rate was observed when a sensitivity analysis was limited to studies with a low risk of bias.For serum lipids,adding ezetimibe to statin or fenofibrate might further reduce the LDL?C levels(MD-16.79 mg/dL,95% CI-17.36 to-16.23;17,854 participants;21 studies),total cholesterol levels(MD-19.70 mg/dL,95% CI-20.48 to-18.92;16,330 participants;18 studies)and triglyceride levels(MD-27.58,95% CI-33.67 to-21.49;1,253 participants;12 studies),and likely increase the high?density lipoprotein cholesterol levels(MD 0.66 mg/dL,95% CI 0.30 to 1.03;16,434 participants;18 studies);however,substantial heterogeneity was detected in most analyses.In terms of safety,adding ezetimibe to statins may make little or no difference in the risk of hepatopathy(RR 1.14,95% CI 0.96 to 1.35;20,687 participants;4 studies;low ?quality evidence).It is uncertain whether ezetimibe increase or decrease the risk of myopathy(RR 1.31,95% CI 0.72 to 2.38;20,581 participants;3 studies;very low?quality evidence)and rhabdomyolysis,given the wide CIs and low event rate.Little or no difference in the risk of cancer,gallbladder?related disease and discontinuation due to adverse events were observed between treatment groups.The subgroup analyses showed no difference in primary outcomes(MACE and all?cause mortality)between the participants with or without ASCVD.The subgroup analyses showed no difference in primary outcomes(MACE and all?cause mortality)between the long?term studies(> 2 years)and short?term studies(? 2 years).The sensitivity analyses suggested little change in the overall results.None of the included studies reported on health?related quality of life.ConclusionsModerate? to high?quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints,primarily driven by a reduction in non?fatal MI and non?fatal stroke,but it has little or no effect on clinical fatal endpoints.The cardiovascular benefit of ezetimibe might involve the reduction of LDL?C,total cholesterol and triglycerides.There is insufficient evidence to determine whether ezetimibe increases the risk of adverse events due to the low and very low quality of the evidence.The evidence for beneficial effects was mainly obtained from individuals with established atherosclerotic cardiovascular disease(ASCVD,predominantly with acute coronary syndrome)administered ezetimibe plus statins.However,there is limited evidence regarding the role of ezetimibe in primary prevention and the effects of ezetimibe monotherapy in the prevention of CVD,and these topics thus requires further investigation. |
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