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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%;
20、 RR 1.01; 95%CI, 0.94-1.09 vs. ramipril). combination: 1386 (16.3%; RR 0.99; 95% CI, 0.92-1.07 vs. ramipril); 3.side effects: telmisartan: cough (1.1% vs. 4.2%, P0.001 vs. ramipril ) angioedema (0.1% vs. 0.3%, P=0.01 vs. ramipril ) hypotensive symptoms (2.6% vs. 1.7%, P0.001 vs. ramipril ); syncope:
21、 the same in the two groups (0.2% vs. ramipril ). combination : hypotensive symptoms (4.8% vs. 1.7%, P0.001 vs. ramipril ), syncope (0.3% vs. 0.2%, P=0.03 vs. ramipril ), renal dysfunction (13.5% vs. 10.2%, P0.001 vs. ramipril ).,KaplanMeier Curves for the Primary Outcome in the Three Study Groups.,
22、Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. Adding an angiotensin-receptor blocker to an angiotensin-convertingenzyme inhibitor may produce a greater reduction in blood pressure, but it may not reduce cardiov
23、ascular risk and it increases the risk of other adverse events. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.,ONTARGET,ACCORD,ACCORD (Action to Control Cardiovascular Risk in Diabetes) NEJM 2008，358:2545-2559
24、 Strategy：the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus.,ACCORD,Methods In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive target
25、ing glycated hemoglobin Intensive therapy：below 6.0%； Standard therapy： 7.0 to 7.9%. Primary outcome： composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensiv
26、e therapy after a mean of 3.5 years of follow-up.,ACCORD,At 1 year Results Intensive Standard HR，95% CI P Stable median Glycated hemoglobin 6.4% 7.5% Primary outcome（n） 352 371 0.90 0.78-1.04; 0.16 Death （n） 257 203 1.22; 1.01-1.46 0.04 Hypoglycemia requiring assistance and weight gain of more than
27、10 kg were more frequent in the intensive-therapy group (P0.001).,ACCORD,As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify
28、 a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes,ADVANCE,ADVANCE (Action in Diabetes and Vascular Disease: Preterax (复方:配德利锭: PERINDOPRIL培哚普利 1.669mg +吲哚帕胺INDAPAMIDE 0.625mg ) and Diamicron Modified Release Controlled Evaluation. Strategy：the u
29、se of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus.,ADVANCE,The ADVANCE studys findings indicate that its strategy may reduce the risk of worsening renal function at the cost of an excess risk of hypoglycemic events.,torcetrap
30、ib ：a promising agent that lowered LDL cholesterol levels and raised high-density lipoprotein (HDL) cholesterol levels. the tendency of torcetrapib to cause blood pressure to rise and potassium levels to fall attracted much more attention after December 2006 than it had previously.,ILLUMINATE Trial
31、(Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events),Patients receiving torcetrapib plus atorvastatin had a higher mortality rate than those receiving atorvastatin alone despite 72% increases in HDL levels and 25% decreases in LDL levels. （Nissen SE, Tardif JC
32、, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-1316） on December 2, 2006, the day Pfizer stopped ILLUMINATE trial and all other trials involving torcetrapib.,Some strategies are known to improve patient outcomes, whereas others
33、are known to affect only risk-factor levels or other intermediate outcomes. We are now beginning to appreciate that a strategys effect on a risk factor may not predict its effect on patient outcomes.,Lifestyle interventions may have few risks, but we cannot assume the same for drugs and drug-related
34、 risks are not always known or appreciated. considerations of the risks of disease adverse consequences posed by the intervention.,an intervention designed to protect against that outcome is unlikely to provide substantial benefit so if the intervention carries even a small risk, this risk can offse
35、t or even outweigh the benefit. In sicker patients and those with more complex conditions, certain interventions (such as maintenance of tight glucose control) may be more likely to produce adverse effects than they would in healthier patients, either directly or through their effect on adherence.,F
36、ocus on patient outcomes, improvement, not just intermediate outcomes, not just on surrogate end points.,Individualized Medicine 3P Medicine：personalized predictive preventive,“Between the healthcare we have and the care we could have lies not just a gap, but a chasm(大峡谷）.” “The lag between the disc
37、overy of more efficacious forms of treatment and their incorporation into routine patient care is unnecessarily long, in the range of about 15-20 years.”,Major Challenge: Applying What We Know,Study design based on Pharmacogenomics Epigenetics/epigenomics Telomere: short or longer,在人群的遗传素质是相对稳定的情况下，
38、我国疾病谱和发病率发生巨大改变。这种变化表明环境对疾病有着巨大的影响。 对结肠癌、脑中风、冠心病和II型糖尿病等多种复杂性疾病的研究发现，至少70的患者受不良的“环境因素”影响，如偏食、超重、不运动和抽烟。而且，如果改变不良生活习惯，可大大地降低这些疾病。,表观遗传学定义：“在基因组序列不变的情况下，可以决定基因表达与否并可稳定遗传下去的调控密码”。 表遗传学内容包括： DNA甲基化、 基因组印记、 染色质组蛋白修饰、 隔离蛋白 非编码RNA (包括microRNA) 等 DNA序列以外的各种调控方式，任何一方面的异常都将影响染色质结构和基因表达，导致复杂综合征、多因素疾病。 环境因素的影响短期内或许难以造成基因序列的改变，但却可以改变表观遗传密码，并将这种“烙印”传递给下一代。,科技部中德分子医学研究室暨教育部基因与临床重点室 科技部/国家外专局国家级国际合作研究中心,