事与愿违的大型临床试验结果告诉了我们什麽

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,What We have Learned from the Failure of Large Clinical Trials?,事与愿违的大型临床试验结果告诉了我们什麽?,HUI Rutai 惠汝太,Beijing FuWai Hospital,China,北京阜外医院高血压中心主任,prioritizes target levels of some risk factors:,plasma sugar,blood presure,cholestrol,Womens Health Initiative,RCT,revealed that hormone-replacement therapy,which reduces LDL cholesterol levels,increased the risk of cardiovascular disease.,(,Anderson et al.Effects of conjugated equine estrogen in postmenopausal women with hysterectomy:the Womens Health Initiative Randomized Controlled Trial.JAMA 2004;291:1701-1712,),ENHANCE,ENHANCE:Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial,Hypercholesterolemia,Kastelein et al:NEJM 2021,358:1431-1443;,Correction:NEJM 2021,358:1977,ENHANCE showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin,as compared with simvastatin alone,even though the combination did result in a greater reduction of LDL cholesterol.,Kastelein et al:NEJM 2021,358:1431-1443;,Correction:NEJM 2021,358:1977,Post-trial Study,UKPDS(UK Protective Diabetes Study),Type-2 DM:low plasma glucose,Reduction in microvascular complications.,Whether the therapy can reduce,macrovascular complications?,降糖治疗试验停止后，持续随访10年的结果,Holman et al NEJM 2021:359:,Any DM-related Endpoints：,sudden death，,death from hyperglycemia,hypoglycemia,fatal,non-fatal MI,angina,heart failure,fatal,non-fatal Stroke,renal failure,amputation,vitreous hemorrhage,retinal photo-coagulation,blindness in one eye,hyperglycemia,Hypoglycemia.,Microvascular disease,:,vitreous(玻璃体)hemorrhage,retinal photo-Coagulation(视网膜光凝术,),renal failure,Follow-up 10 years,Sulfonylurea-Insulin Metoformin,Any DM-related,Endpoints 9%(P=0.04)21%(P=0.01),Microvas Dis 24%(P=0.001),MI 15%(P=0.01)33%(P=0.005),Death from,Any cause 13%(P=0.007)27%(P=0.002),与传统限制饮食治疗比较，药物强化治疗,Holman et al NEJM 2021:359:,ADVANCE,The ADVANCE：action in diabetes and vascular disease-preterax and diamicron MR controlled evaluation.Diabetologia 2001;44:1118-1120 Collaborative Group NEJM 2021,358:2560-2572,ADVANCE,11,140 patients with type 2 diabetes;,Grouped:,1.standard glucose control,2.intensive glucose control:gliclazide,(格列齐特,达美康,modified release)plus other drugs as,required to achieve a glycated hemoglobin,value of 6.5%or less.,Primary end points:,posites of major macrovascular events:,death from cardiovascular causes,nonfatal,myocardial infarction,or nonfatal stroke,2.major microvasc events:new or worsening,nephropathy or retinopathy,ADVANCE,After a median of 5 years of follow-up,Intensive Standard HR 95%CI P,Glycated hemoglobin 6.5%7.3%,Combined major,macrovascular&,microvascular events:18.1%,20.0%0.90 0.82-0.98 0.01,Major microvascular,events 9.4%10.9%0.86 0.77-0.97 0.01,Incidence,of nephropathy 4.1%5.2%0.79 0.66-0.93 0.006,ADVANCE,No significant effect on retinopathy(P=0.50).,No significant effects of the type of glucose,control on：major macrovasc.events,death from cardiovasc.causes,death from any cause,Sevre hypoglycemia HR 95%CI P,Intensive 2.7%,1.86 1.42-2.40 0.001,Standard:1.5%,Meta-analysis：Rosiglitazone Avandia,Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus,but its effect on cardiovascular morbidity and mortality has not been determined.,Methods：,The authors searched the published literature,Web site,of FDA,and a clinical-trials registry maintained.,Criteria for inclusion in the meta-analysis included a,study duration of more than 24 weeks,the use of a randomized control group not receiving rosiglitazone,and the availability of outcome data for myocardial infarction and death from cardiovascular causes.Of 116 potentially relevant studies,42 trials met the inclusion criteria.all occurrences of myocardial infarction and death from cardiovascular causes were tabulated.,Meta-analysis：Rosiglitazone Avandia,Results：,In the 42 trials,the mean age of the subjects was approximately 56 years,and the mean baseline glycated hemoglobin level was approximately 8.2%.,In the rosiglitazone group,as compared with the control group,the odds ratio for myocardial infarction was 1.43(95%CI,1.03 to 1.98;P=0.03),and the odds ratio for death from cardiovascular causes was 1.64(95%CI,0.98 to 2.74;P=0.06).,Meta-analysis：Rosiglitazone Avandia,Rosiglitazone improves glucose control,but it may also be associated with increased cardiovascular risk.,(Nissen et al.Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.N Engl J Med 2007;356:2457-2471),ONTARGET,On,going,T,elmisartan,A,lone and in Combination with,R,amipril(雷米普利),G,lobal,E,ndpoint,T,rial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease(,ONTARGET,/TRANSCEND)trials.Am Heart J 2004;148:52-61.,ACEI reduce mortality and morbidity from cardiovascular causes,but the role of ARBs in such patients is unknown.,T