事与愿违的大型临床试验结果告诉了我们什麽课件

1、事与愿违的大型临床试验结果告诉了我们什麽 What We have Learned from the Failure What We have Learned from the Failure of Large Clinical Trials?of Large Clinical Trials? 事与愿违的大型临床试验结果告诉了我们事与愿违的大型临床试验结果告诉了我们什麽什麽? ? HUI Rutai HUI Rutai 惠汝太惠汝太 Beijing FuWai Hospital, ChinaBeijing FuWai Hospital, China事与愿违的大型临床试验结果告诉了我们什麽 pr

2、ioritizes target levels of some risk factors: plasma sugar blood presure cholestrol事与愿违的大型临床试验结果告诉了我们什麽 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 e

3、quine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701-1712) 事与愿违的大型临床试验结果告诉了我们什麽ENHANCE ENHANCE: Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone on the Atherosclerotic Process in Patie

4、nts with Heterozygous Familial Hypercholesterolemia Kastelein et al: NEJM 2008,358:1431-1443; Correction: NEJM 2008,358:1977 事与愿违的大型临床试验结果告诉了我们什麽 ENHANCE showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin, as compared with simvastatin alone, even

5、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事与愿违的大型临床试验结果告诉了我们什麽Post-trial Study UKPDS (UK Protective Diabetes Study) Type-2 DM: low plasma glucose, Reduction in microvascular complications. Whet

6、her the therapy can reduce macrovascular complications? 降糖治疗试验停止后，持续随访降糖治疗试验停止后，持续随访10年的结果年的结果 Holman et al NEJM 2008:359:事与愿违的大型临床试验结果告诉了我们什麽Any DM-related Endpoints： sudden death， death from hyperglycemia, hypoglycemia, fatal, non-fatal MI, angina, heart failure, fatal, non-fatal Stroke, renal fai

7、lure, 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, 事与愿违的大型临床试验结果告诉了我们什麽 Follow-up 10 years Sulfonylurea-Insulin MetoforminAny DM-relate

8、d 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 fromAny cause 13%(P=0.007) 27% (P=0.002)与传统限制饮食治疗比较，药物强化治疗与传统限制饮食治疗比较，药物强化治疗 Holman et al NEJM 2008:359:事与愿违的大型临床试验结果告诉了我们什麽ADVANCE The ADVANCE：action in diabetes and vascular disease - preterax and diamic

9、ron MR controlled evaluation. Diabetologia 2001;44:1118-1120 Collaborative Group NEJM 2008, 358:2560-2572 事与愿违的大型临床试验结果告诉了我们什麽ADVANCE 11,140 patients with type 2 diabetes ; Grouped: 1. standard glucose control 2. intensive glucose control: gliclazide (格列齐特格列齐特, 达美康达美康 modified release) plus other dr

10、ugs as required to achieve a glycated hemoglobin value 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 事与愿违的大型

11、临床试验结果告诉了我们什麽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

12、% 0.79 0.66-0.93 0.006 事与愿违的大型临床试验结果告诉了我们什麽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 PIntensive 2.7%, 1.86 1.42 -2.40 0.001Stan

13、dard: 1.5% 事与愿违的大型临床试验结果告诉了我们什麽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

14、, 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 ca

15、uses. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. all occurrences of myocardial infarction and death from cardiovascular causes were tabulated. 事与愿违的大型临床试验结果告诉了我们什麽Meta-analysis： Rosiglitazone （Avandia） Results： In the 42 trials, the mean age of the subjects was approx

16、imately 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

17、 (95% CI, 0.98 to 2.74; P=0.06). 事与愿违的大型临床试验结果告诉了我们什麽 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 cardiovasc

18、ular causes. N Engl J Med 2007;356:2457-2471)事与愿违的大型临床试验结果告诉了我们什麽ONTARGETOngoing Telmisartan Alone and in Combination with Ramipril(雷米普利雷米普利 ) Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J

19、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 ACEI ramipril, ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. The

20、ONTARGET Investigators, NEJM 358:1547-1559 事与愿违的大型临床试验结果告诉了我们什麽ONTARGETGroups: 1.ramipril 10 mg qd 2.telmisartan 80 mg qd 3. Combination of the two drugsPrimary composite outcome: 1.death from cardiovascular causes, myocardial infarction, stroke, 2.hospitalization for heart failure. 事与愿违的大型临床试验结果告诉了

21、我们什麽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%; RR 1.01; 95%CI, 0.94-1.09 vs. ramipril). combination: 1386 (16.3%; RR 0.99; 95% CI, 0.92-1.

22、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: the same in the two groups (0.2% vs. ramipril ). combination : hypotensive symptoms (4.8% v

23、s. 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 ). 事与愿违的大型临床试验结果告诉了我们什麽KaplanMeier Curves for the Primary Outcome in the Three Study Groups. 事与愿违的大型临床试验结果告诉了我们什麽 Telmisartan was equivalent to ramipril in patients

24、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 cardiovascular risk and it increases the risk of other adv

25、erse 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事与愿违的大型临床试验结果告诉了我们什麽ACCORD ACCORD (Action to Control Cardiovascular Risk in Diabetes) NEJM 2008，358:2545-2559 Strategy：the use of multiple me

26、dications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus. 事与愿违的大型临床试验结果告诉了我们什麽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 targeting glycated

27、 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 intensive therapy af

28、ter a mean of 3.5 years of follow-up. 事与愿违的大型临床试验结果告诉了我们什麽ACCORDAt 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 mor

29、e than 10 kg were more frequent in the intensive-therapy group (P0.001). 事与愿违的大型临床试验结果告诉了我们什麽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 even

30、ts. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes事与愿违的大型临床试验结果告诉了我们什麽ADVANCE ADVANCE (Action in Diabetes and Vascular Disease: Preterax (复方复方:配德利锭配德利锭: PERINDOPRIL培哚普利培哚普利 1.669mg +吲哚帕胺吲哚帕胺INDAPAMIDE 0.625mg ) and Diam

31、icron Modified Release Controlled Evaluation. Strategy：the use of multiple medications to achieve tight glucose control would improve outcomes in patients with type 2 diabetes mellitus.事与愿违的大型临床试验结果告诉了我们什麽ADVANCE The ADVANCE studys findings indicate that its strategy may reduce the risk of worsening

32、 renal function at the cost of an excess risk of hypoglycemic events. 事与愿违的大型临床试验结果告诉了我们什麽 torcetrapib ：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

33、 to fall attracted much more attention after December 2006 than it had previously. 事与愿违的大型临床试验结果告诉了我们什麽 ILLUMINATE Trial (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events)事与愿违的大型临床试验结果告诉了我们什麽 Patients receiving torcetrapib plus atorvastatin had a higher mort

34、ality rate than those receiving atorvastatin alone despite 72% increases in HDL levels and 25% decreases in LDL levels. （Nissen SE, Tardif JC, 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 Pfize

35、r stopped ILLUMINATE trial and all other trials involving torcetrapib.事与愿违的大型临床试验结果告诉了我们什麽 Some strategies are known to improve patient outcomes, whereas others are known to affect only risk-factor levels or other intermediate outcomes. We are now beginning to appreciate that a strategys effect on a

36、 risk factor may not predict its effect on patient outcomes. 事与愿违的大型临床试验结果告诉了我们什麽 Lifestyle interventions may have few risks, but we cannot assume the same for drugs and drug-related risks are not always known or appreciated. considerations of the risks of disease adverse consequences posed by the i

37、ntervention. 事与愿违的大型临床试验结果告诉了我们什麽 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 offset or even outweigh the benefit. In sicker patients and those with more complex conditions, certai

38、n 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. 事与愿违的大型临床试验结果告诉了我们什麽 Focus on patient outcomes, improvement, not just intermediate outcomes, not just on surrogate end points. 事与愿违的大型临床试验结果告诉了我们什麽 Individualized Medicine 3P Medicine：personalized predictive preventive事与愿违的大型临床试验结果告诉了我们什麽“Between the h