事与愿违的大型临床试验结果告诉了我们什麽.ppt
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1、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
2、, 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 Combin
3、ation Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia Kastelein et al: NEJM 2008,358:1431-1443; Correction: NEJM 2008,358:1977,ENHANCE showed that ezetimibe did not reduce the progression of arter
4、iosclerosis 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 2008,358:1431-1443; Correction: NEJM 2008,358:1977,Post-trial Study,UKPDS (UK Protective Diabetes Study) Type-2 DM:
5、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 2008:359:,Any DM-related Endpoints: sudden death, death from hyperglycemia, hypoglycemia, fatal, non-fatal MI, angina, heart failure, fatal
6、, 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
7、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 2008:359:,ADVANCE,The ADVANCE:action in diabetes and vascular disease - preterax and diamicron MR controlled evalu
8、ation. Diabetologia 2001;44:1118-1120 Collaborative Group NEJM 2008, 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 v
9、alue of 6.5% or less. Primary end points: 1. composites 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
10、 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
11、=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
12、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 d
13、uration 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 myocard
14、ial 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 compar
15、ed 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
16、 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,Ongoing Telmisartan Alone and in Combination with Ramipril(雷米普利 ) Global Endpoint Trial/Telmi
17、sartan 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. The aim of the study was to compare the
18、ACEI ramipril, ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. The ONTARGET Investigators, NEJM 358:1547-1559,ONTARGET,Groups: 1.ramipril 10 mg qd 2.telmisartan 80 mg qd 3. Combination of the two drugs Primary composite outcome: 1.death
19、from cardiovascular causes, myocardial infarction, stroke, 2.hospitalization for heart failure.,Results,A median follow-up of 56 months, vs. ramipril telmisartan combination 1. Mean blood ressure 0.9/0.6 mm Hg 2.4/1.4 mm Hg greater greater 2. outcome ramipril: 1412 (16.5%), telmisartan: 1423 (16.7%;
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