2008调脂治疗进展与回顾.ppt
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1、,2008调脂治疗进展与回顾,曲 鹏 大连医科大学附属第二医院,主要内容,新型调脂药胆固醇吸收抑制剂-ENHANCE、SEAS TRIAL带给我们的思考 他汀能否改善慢性心力衰竭患者预后? 他汀多途径抗动脉粥样硬化干预炎症反应 评估AS 风险的指标:替代终点 or/and 临床终点? LDL-C-抗AS首要干预目标 依托循证,重返他汀时代,ENHANCE TRIAL Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia,Kastelein, et al, N Eng J Med 358:1431-1443
2、April 3, 2008,BACKGROUND Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of LDL-c when added to statin treatment. However, the effect of Ezetimibe on the progression of atherosclerosis is unknown,ENHANCE Study Design,Simvastatin 80 mg,RANDOMI ZAT I ON,0,24,Months,3,6,9,12,15,18,21,Pre-
3、randomization Phase,FH: LDL-c 210 mg/dL,Screening and Fibrate Washout,Placebo Lead-In/ Drug Washout,Weeks,-6,-10 to -7,Ezetimibe 10 mg-Simvastatin 80 mg,IMT assessment,ENHANCE cIMT Methodology Carotid Intima-Media thickness (cIMT) measurements,Measurements were made at a predefined angle of insonati
4、on Only the far-walls of all segments were imaged Images were stored in DICOM for offline image analyses,Months,LDL-C,-40,0,6,12,18,24,-50,-60,-70,0,-10,-20,-30,10,Percentage change from baseline,P0.01,-16.5 % incremental reduction,Other Lipids and Apolipoproteins,hsCRP,-26 % incremental reduction,B
5、aseline 24 months (mg/L) (mg/L) Simva 1.7(0.8-4.1) 1.2(0.6-2.4) Eze-Simva 1.7(0.8-3-9) 0.9(0.5-1.9),Mean cIMT during 24 months of therapy Longitudinal, repeated measures analysis,Mean IMT (mm),ENHANCE TRIAL,The addition of Ezetimibe to Simvastatin did lead to expected changes in LDL-C and hsCRP, but
6、 did not reduce any cIMT parameter The reasons for this discrepancy currently remains unknown,Conclusion:,SEAS TRIAL Simvastatin & Ezetimibe in Aortic Stenosis,BACKGROUND: Previous studies assessing the impact of statin therapy on aortic valve stenosis (AoVS) have demonstrated mixed results. PURPOSE
7、: To determine the effects of long term intensive cholesterol lowing on AoVS. DESIGN: Randomized, double blind study of 1,873 patients with mild moderate, asympomatic aortic stenosis randomized to: 40mg simvastatin plus 10mg of ezetimibe(n=944) or placebo(n=929). Median follow up=52.2 months.,Rosseb
8、o NEJM 2008:359,SEAS TRIAL Simvastatin & Ezetimibe in Aortic Stenosis,Primary Endpoint: Composite of CV events: CV death; AoV replacement, nonfatal MI, hospitalization for HF,USA,CABG,PCI & non-hemorrhagic stroke. Secondary Endpoint: Events related to AoVS & ischemic CV events,SEAS TRIAL Simvastatin
9、 & Ezetimibe in Aortic Stenosis,28.8%,Percent,28.3%,29.9%,Primary outcome,AoV Replacement,35.3%,38.2%,Ischemic Events:SE(n=148)vs. P (n=187)p=0.02 Cancer occurrence: SE(n=105)vs. P (n=70)p=0.01,SEAS TRIAL Simvastatin & Ezetimibe in Aortic Stenosis,Conclusion: Smivastatin/Ezetimibe therapy do not red
10、uce combined AoV events therapy did reduce the incidence of ischemic CV events. Implications: Lipid lowing therapy can be used to reduce the risk of ischemic CV events. Cancer incidence needs to be further analyzed.,主要内容,新型调脂药胆固醇吸收抑制剂-ENHANCE、SEAS 带给我们的思考 他汀能否改善慢性心力衰竭患者预后? 他汀多途径抗动脉粥样硬化干预炎症反应 评估AS 风险
11、的指标:替代终点 or/and 临床终点? LDL-C-抗AS首要干预目标 依托循证,重返他汀时代,The GISSI-HF TRIAL Effects of rosuvastatin in patients with symptomatic chronic HF,BACKGROUND: Pleiotropic actions of statins may target components of the complex syndrome of HF. While observational studies, small RCTs etc, suggest a decrease in CV m
12、ortality in HF patients, large RCTs are needed. PURPOSE: To investigate the impact of rosuvastation in HF pts.,The GISSI-HF TRIAL Effects of rosuvastatin in patients with symptomatic chronic HF,DESIGN: Prospective, multicenter, randomized, double blind, placebo controlled study of 4,574 patients wit
13、h symptomatic HF of any etiology & any level of LVEF randomized to: Rosuvastatin (Rosu) 10mg po daily (n=2,285) & placebo (n=2,289). Median follow-up=3.9 yrs. Primary Endpoint: All Cause Mortality Secondary Endpoint: All Cause Mortality or hospitalization for CV reasons.,Presented at ESC 2008/Gianni
14、 Tognoni MD,The GISSI-HF TRIAL Effects of rosuvastatin in patients with symptomatic chronic HF,28.8%,Probabillity of Death,28.1%,28.8%,57.1%,56.1%,All Cause Mortality,All Cause Mortality or Hospitalization for CV Reasons,The GISSI-HF TRIAL Effects of rosuvastatin in patients with symptomatic chronic
15、 HF,Conclusion: Rosuvastation does not improve clinical outcomes in chronic HF pts of any age, etiology & systolic function level. Implications: No need to prescribe statins in HF pts of no-ischemic etiology. MD discretion should be used on discontinuing statins in HF pts with ischemic etiology.,主要内
16、容,新型调脂药胆固醇吸收抑制剂-ENHANCE、SEAS 带给我们的思考 他汀能否改善慢性心力衰竭患者预后? 他汀多途径抗动脉粥样硬化干预炎症反应 评估AS 风险的指标:替代终点 or/and 临床终点? LDL-C-抗AS首要干预目标 依托循证,重返他汀时代,Nature 2008;451:904-913 动脉粥样硬化的可能干预点:脂质代谢和炎症反应,At present, the two main conceptual approaches to therapy for atherosclerosis are manipulation of plasma lipoprotein metab
17、olism or cellular cholesterol metabolism, and manipulation of inflammatory processes. 迄今为止,理论上干预动脉粥样硬化的两大治疗手段分别是:干预脂质代谢和干预炎症反应,预测心血管风险的可能炎性指标 粘附分子 细胞因子 纤维蛋白原 SAA CRP WBC计数 其他(如血沉),在各种炎性指标中,CRP受到的关注最多,Circulation 2003;107;499-511,目前的证据支持可将CRP作为临床检测指标,斑块体积改变 (mm3),Nissen, Ganz NEJM 2005; 352:29-38,REV
18、ERSAL进一步分析提示: 同时降LDL-C和CRP,斑块逆转更多,进展,逆转,LDL CRP,LDL CRP,LDL CRP,LDL CRP,+8mm3,+2mm3,- 1mm3,- 2mm3,中位数LDL降低37.1% (LDL=94mg/dl) 中位数CRP降低21.4% (CRP2.3mg/L),-4,-2,0,2,4,6,8,10,PROVE IT研究提示: 同时降LDL-C和CRP,心血管获益越多,心肌梗死再发或冠心病死亡(%),LDL-C 70 mg/dL, CRP 2 mg/L,LDL-C 2 mg/L,随 访 时 间 (年),LDL-C 70 mg/dL, CRP 2 mg/
19、L,LDL-C 70 mg/dL, CRP 2 mg/L,0.0,0.5,1.0,1.5,2.0,2.5,0.0,0.5,1.0,1.5,2.0,2.5,0.0,0.5,1.0,1.5,2.0,2.5,0.00,0.04,0.02,0.06,0.08,0.10,LDL-C 70 mg/dL, CRP 1 mg/L,Ridker et al. NEJM 2005; 352:20-28,Nissen SE. JAMA. 2004;292:1365-1367,MIRACL:更多降低CRP似乎是立普妥强化治疗更多、更早获益的原因,* 随机分组后120天时的测量结果,JUPITER TRIAL Just
20、ification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin,JUPITER是评价他汀类对LDL-C水平正常或低于正常、但CRP水平升高导致心血管风险升高个体的治疗效果的首个大规模、前瞻性的临床研究 该研究针对CRP水平升高导致心血管(CV)风险升高、但根据当前治疗指南不符合降脂治疗指征的个体,和安慰剂相比,评估瑞舒伐他汀(可定 ) 20mg长期治疗是否能降低首次主要心血管事件的发生,Ridker P et al. N Eng J Med 2008;35
21、9: 2195-2207,JUPITER 研究设计,血脂 CRP 耐受性,血脂 CRP 耐受性 HbA1C,安慰剂 导入,1 6,2 4,3 0,4 13,结束,6-每个月,随访: 周数:,随机化,血脂 CRP 耐受性,瑞舒伐他汀 20 mg (n=8901),安慰剂 (n=8901),导入/ 符合要求,既往无CAD病史 男性 50 岁 女性 60 岁 LDL-C 130 mg/dL CRP 2.0 mg/L,CAD=冠状动脉疾病; LDL-C=低密度脂蛋白胆固醇; CRP=C反应蛋白; HbA1c=糖基化血红蛋白,中位随访时间1.9年,Ridker P et al. N Eng J Med
22、2008;359: 2195-2207,JUPITER 研究终点,主要终点 首次发生主要心血管事件的时间,包括: 心血管死亡 卒中 心梗 不稳定性心绞痛 动脉血运重建 次要终点: 总死亡率 非心血管死亡率 发生糖尿病 静脉血栓栓塞事件的发生 骨折 由于不良反应而导致中断研究药物,Ridker PM. Circulation 2003; 108: 22922297,0,1,2,3,4,5,6,7,8,9,0,1,2,3,4,5,年,安慰剂,瑞舒伐他汀20 mg,JUPITER 主要终点 首次发生心血管死亡、非致死性卒中、非致死性心梗、不稳定性心绞痛或动脉血运重建的时间,出现主要终点患者的百分比%
23、,存在风险的患者人数 瑞舒伐他汀 8901 8412 3893 1353 538 157 安慰剂 8901 8353 3872 1333 531 174,危险度0.56 (95% 置信区间 0.46-0.69) P0.00001,Ridker P et al. N Eng J Med 2008;359: 2195-2207,2年的NNT = 95 5年的NNT* = 25,*以Altman和Anderson的方法为基础外推的数据,0,1,2,3,4,5,6,7,0,1,2,3,4,5,年,安慰剂,瑞舒伐他汀 20mg,JUPITER 总死亡率 全因死亡,总体亡率百分比,存在风险的患者人数 瑞舒
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