-降胆固醇治疗获益的新证据——SHARP研究的启示课件

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text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth 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Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,更多医学精品尽在医学吧,降胆固醇治疗获益的新证据,SHARP,研究的启示,解放军总医院,终末期肾病患者心血管死亡率高,Adapted from Foley RN et al.,Am J Kidney Dis,. 1998;32(5 Suppl 3):S112S119.,GP Male,GP Female,GP Black,GP White,Dialysis Male,Dialysis Female,Dialysis Black,Dialysis White,Transplant,Age (years),年死亡率,(%),总体人群（,GP,）的心血管死亡率（,NCHS,）和进行透析或移植的人群心血管死亡率（,USRDS,）的比较,25-34,35-44,45-54,55-64,65-74,75-84,85,0.001,0.01,0.1,1,10,100,2010,大规模荟萃分析：,eGFR,和蛋白尿与全因死亡及心血管死亡密切相关,入选,14,项白蛋白,/,肌酐,(ACR),测量研究,(n=105,872),；,7,项,eGFR,测量研究,(n=1,128,310),Lancet 2010; 375: 207381,所有原因死亡，,eGFR,所有原因死亡，,ACR,心血管死亡，,eGFR,心血管死亡，,ACR,eGFR (ml/min/1.73m,2,),ACR (ml/g mg/mmol),HR (95%CI),HR (95%CI),线性相关,显著相关,线性相关,显著相关,慢性肾病患者不同阶段的血脂谱分布,*,Mainly in individuals with high-molecular-weight apolipoprotein(a) phenotypes.,Tsimihodimos V et al.,Am J Nephrol,. 2008;28(6):958973.,LDL-C,sdLDL,TRG,HDL-C,Lp(a),CKD,透析之前,(Stages 3-4),OR,肾病综合征,(Stages 3-4),OR,OR OR,血透,(Stage 5),OR,腹透,(Stage 5),肾移植,(Stage 5),*,*,Study or subcategory,Statinn,Placebon,Relative risk(random) (95% CI),Weight(%),Relative risk(random) (95% CI),Pre-dialysis patients,Subtotal (95% CI),9622,9741,76.43,0.75 (0.66 to 0.85),Dialysis patients,Subtotal (95% CI),619,636,19.33,0.86 (0.74 to 0.99),Transplant patients,Subtotal (95% CI),1050,1052,3.69,0.70 (0.48 to 1.01),Mixed population (pre-dialysis and dialysis patients),Subtotal (95% CI),70,73,0.56,0.63 (0.24 to 1.63),Total (95% CI),11,361,11,502,100.00,0.78 (0.73 to 0.84),*Only studies with at least one event are included in the plot.,Strippoli GF et al.,BMJ,. 2008;336:645651.,Cochrane,荟萃分析,心血管事件,:,与安慰剂或未治疗相比他汀在未透析、透析及移植患者中的疗效,*,Favorsstatin,Favorsplacebo,Patients with Earlier Stages of CKD May Realize Greater Benefit,*,Only studies with at least one event are included in the plot.,Strippoli GF et al.,BMJ,. 2008;336:645651.,Study or subcategory,Statinn,Placebon,Relative risk(random) (95% CI),Weight(%),Relative risk(random) (95% CI),Pre-dialysis patients,Subtotal (95% CI),9001,9084,67.14,0.80 (0.70 to 0.90),Dialysis patients,Subtotal (95% CI),696,708,22.98,0.83 (0.67 to 1.02),Transplant patients,Subtotal (95% CI),1127,1128,6.27,0.68 (0.46 to 1.03),Mixed population (pre-dialysis and dialysis patients),Subtotal (95% CI),70,73,3.61,1.41 (0.83 to 2.41),Total (95% CI),10,894,10,993,100.00,0.81 (0.73 to 0.90),Cochrane,荟萃分析,心血管死亡,:,与安慰剂或未治疗相比他汀在未透析、透析及移植患者中的疗效,* *,Favorsstatin,Favorsplacebo,Patients with Earlier Stages of CKD May Realize Greater Benefit,心肾保护研究（,SHARP,）结果,Colin Baigent, Martin Landray,SHARP,研究者代表,依折麦布辛伐他汀片是处方药品，在全世界,79,个国家,/,地区上市。因各国家,/,地区的法律、药品审核和其他环境各不相同，依折麦布辛伐他汀片在各国家,/,地区获得批准的适应症也各不相同。在中国大陆地区，目前葆至能,（依折麦布辛伐他汀片）的批准适应症仅为原发性高胆固醇血症和纯合子家族性高胆固醇血症。本资料所收集的信息来自不同国家,/,地区，因此并不表示其在中国大陆地区也适用。处方依折麦布辛伐他汀片前请详细阅读产品说明书。特别提示：在中国大陆地区，目前葆至能,的批准适应症不包括慢性肾病。,SHARP,：研究原理,慢性肾病患者的血管事件风险升高，被之前大部分临床研究排除,在其他人群中已被阐明的降,LDL-C,的益处并不能直接应用到慢性肾病患者,尚未确立胆固醇水平与血管疾病风险之间的关系,血管疾病模式是非典型性的，大部分属非动脉粥样硬化性病变,以往的慢性肾病降,LDL-C,治疗研究尚未得出结论,SHARP,：降,LDL-C,的评价,中位随访,4.9,年,随机分组,（,9438,）,随机分组,（,886,）,依折麦布,10mg/,辛伐他汀,20mg,（,4193),辛伐他汀,20mg,（,1054),安慰剂,（,4191,）,未再次随机分组,（,168,）,依折麦布,/,辛伐他汀,（,4650),安慰剂,（,4620,）,基线血脂水平,Am Heart J 2010;0:1-10.e10,SHARP,：基础文献和数据分析计划,辛伐他汀单药治疗,1,年,LDL-C,较基线降低,30 mg/dL,而依折麦布,/,辛伐他汀,LDL-C,较基线降低,43 mg/dL,在试验第,1,年，辛伐他汀单药治疗较安慰剂组进一步降低,LDL-C28%,，依折麦布,/,辛伐他汀较安慰剂进一步降低,LDL-C40%,，较辛伐他汀单药治疗进一步降低,LDL-C30%,证实了依折麦布联合辛伐他汀的安全性（,1,年结果）,在主要结果解盲之前，数据分析的修订计划已作为附录发表,心肾保护研究（,SHARP,）：随机临床研究以评估,9,438,名慢性肾病患者的降低密度脂蛋白胆固醇的效果,SHARP,协作组,Am Heart J 2010;0:1-10.e10,辛伐他汀,/,依折麦布在,2.5,年时，对于,LDL,-C,和的作用,Biochemical parameter,Simv/Eze,Placebo,Absolute difference,Percentage difference,p,Total cholesterol,3.66,4.73,-1.07,-23%,0.0001,LDL cholesterol,1.80,2.65,-0.85,-32%,0.0001,HDL cholesterol,1.14,1.13,0.02,2%,0.03,Non-HDL cholesterol,2.52,3.60,-1.08,-30%,0.0001,Triglycerides,1.84,2.12,-0.28,-13%,0.0001,Apolipoprotein B,70,93,-23,-24%,0.0001,Apolipoprotein A,1,145,143,2,1%,0.003,SHARP,：研究中期的依从性和,LDL-C,降幅,依折麦布,/,辛伐他汀,安慰剂,依从性,66%,64%,非研究他汀类药物,5%,8%,任何降脂治疗,71%,8%,2/3,依从性,32 mg/dL,的,LDL-C,降幅，,2/3,的依从性，,等同于5,0,mg/dL,，,100%,的依从性,SHARP,：主要结果,关键结果,主要动脉粥样硬化事件（冠心病死亡，心肌梗 死，非出血性卒中，或任何血运重建术）,次要结果,主要血管事件（心源性死亡，心肌梗死，任何 脑卒中，或任何血运重建术）,主要动脉粥样硬化事件的各个组份,主要肾脏结果,终末期肾脏疾病（透析或移植）,0,1,2,3,4,5,随访年数,0,5,10,15,20,25,事件发生率（,%,）,风险比,0.83 (0.74 0.94),Logrank 2P=0.0022,安慰剂,依折麦布,/,辛伐他汀,SHARP,：主要动脉粥样硬化事件,CTT,：对主要动脉粥样硬化事件的影响,动脉粥样硬化事件发生率的比例减少（,98%,置信区间）,0%,5%,10%,15%,20%,25%,30%,他汀比对照组,(21,项试验,),治疗组之间的平均,LDL,胆固醇差异（,mg/dL,）,SHARP,32 mg/dL,0,20,40,10,30,他汀不同剂量比较,（,5,项试验）,CTT,（,Cholesterol Treatment Trialists,）,大型他汀类药物胆固醇治疗临床实验荟萃分析,Available online November 9, 2010;,N=170,000,SHARP,风险降低,17%,预测的降幅结果,SHARP,：死亡原因分析,风险比,& 95% CI,事件,安慰剂,依折麦布,/,辛伐他汀,(n=4620),(n=4650),冠状动脉疾病,91,(2.0%),90,(1.9%),其他心脏疾病,162,(3.5%),182,(3.9%),亚组总计：所有心源性死亡,253,(5.4%),272,(5.9%),7.4% SE 8.4,减少,(p=0.38),脑卒中,68,(1.5%),78,(1.7%),其他血管,40,(0.9%),38,(0.8%),亚组总计：所有血管性死亡,361,(7.8%),388,(8.4%),7.3% SE 7.0,减少,(p=0.30),癌症,150,(3.2%),128,(2.8%),肾病,164,(3.5%),173,(3.7%),其他非血管性,亚组总计：所有非血管性死亡,668,(14.4%),612,(13.2%),8.6% SE 5.8,增加,(p=0.14),不明原因,113,(2.4%),115,(2.5%),总计：全因死亡,1142,(24.6%),1115,(24.1%),1.9% SE 4.2,增加,(p=0.65),0.6,0.8,1.0,1.2,1.4,354,(7.6%),311,(6.7%),依折麦布,/,辛伐他汀,更好,安慰剂,更好,SHARP,：各亚组的疗效,在最初随机接受依折麦布,/,辛伐他汀或安慰剂的,8384,名患者中， 主要的血管事件风险比是,0.84 (95%,置信区间,0.75 0.93; p=0.0010),在研究的全部亚组中，主要动脉粥样硬化事件均有降低（包括非透析和透析治疗的患者）,风险比,& 95% CI,安慰剂,依折麦布,/,辛伐他汀,(n=4620),(n=4650),非透析,(n=6247),296,(9.5%),373,(11.9%),透析,(n=3023),230,(15.0%),246,(16.5%),任何患者,526,(11.3%),619,(13.4%),16.5% SE 5.4,降低,(p=0.0022),0.6,0.8,1.0,1.2,1.4,SHARP,：主要动脉粥样硬化事件，,按随机时的肾功能状况,非透析或透析治疗患者之间无显著性差异,(p=0.25),依折麦布,/,辛伐他汀,更好,安慰剂,更好,0.5,0.75,1,1.5,2,Trial,事件,(%,患者,),Allocated,LDL-C reduction,Allocated,control,Risk ratio (RR) per,mmol/L LDL-C reduction,p,LDL-C reduction,better,Control better,99% or,95% CI,SHARP,和其他研究的综合分析,:,非致死性心肌梗死,4D,33 (1.91),35 (2.02),AURORA,91 (1.97),107 (2.33),ALERT,54 (1.03),65 (1.24),SHARP,134 (0.71),159 (0.85),c,3,2,=,0.3,(p = 0.96),小计,: 4,肾脏相关研究,312 (1.02),366 (1.21),0.83 (0.70 - 0.98),0.03,23,项其他研究,3307 (0.97),4386 (1.29),0.73 (0.70 - 0.76),0.0001,所有研究,3619 (0.97),4752 (1.29),0.74 (0.70 - 0.77),0.0001,肾脏相关研究和非肾脏相关研究的差别,c,1,2,=,2.2 (p = 0.14),0.5,0.75,1,1.5,2,Trial,事件,(%,患者,),Allocated,LDL-C reduction,Allocated,control,Risk ratio (RR) per,mmol/L LDL-C reduction,p,LDL-C reduction,better,Control better,99% or,95% CI,SHARP,和其他研究的,综合分析,:,非致死性非出血性卒中,4D,31 (1.80),29 (1.67),AURORA,46 (0.99),39 (0.84),ALERT,51 (0.97),40 (0.76),SHARP,97 (0.51),128 (0.68),c,3,2,=,6.4,(p = 0.09),小计,: 4,肾脏相关研究,225 (0.73),236 (0.77),0.95 (0.77- 1.17),0.65,23,项其他研究,1624 (0.48),2052 (0.61),0.78 (0.73 - 0.83),0.0001,所有研究,1849 (0.50),2288 (0.62),0.79 (0.74 - 0.84),0.0001,肾脏相关研究和非肾脏相关研究的差别,c,1,2,=,3.4 (p = 0.07),0.5,0.75,1,1.5,2,Trial,事件,(%,患者,),Allocated,LDL-C reduction,Allocated,control,Risk ratio (RR) per,mmol/L LDL-C reduction,p,LDL-C reduction,better,Control better,99% or,95% CI,SHARP,和其他研究的,综合分析,:,血管性死亡,4D,151 (8.52),167 (9.36),AURORA,324 (6.87),324 (6.86),ALERT,66 (1.23),73 (1.36),SHARP,361 (1.82),388 (1.97),c,3,2,=,0.9,(p = 0.82),小计,: 4,肾脏相关研究,902 (2.85),952 (3.01),0.94 (0.85 - 1.04),0.27,23,项其他研究,3679 (1.05),4230 (1.21),0.85 (0.81 - 0.89),0.0001,所有研究,4581 (1.20),5182 (1.36),0.86 (0.83 - 0.90),10,倍但,40,倍正常上限,17 (0.4%),16 (0.3%),CK 40,倍正常上限,4 (0.1%),5 (0.1%),肝炎,21 (0.5%),18 (0.4%),ALT/AST,持续升高,3,倍正常上限,30 (0.6%),26 (0.6%),胆结石合并症,85 (1.8%),76 (1.6%),胆结石导致的其他住院治疗,21 (0.5%),30 (0.6%),胰腺炎，不伴有胆结石,12 (0.3%),17 (0.4%),SHARP,：结论,依折麦布,/,辛伐他汀治疗的三分之二的依从性使主要动脉粥样硬化事件的风险减少了,17%,（与以往他汀类药物临床试验的荟萃分析结果一致）,100%,的依从性可使主要动脉粥样硬化事件的风险减少四分之一，每,1000,名接受,5,年治疗的患者中，可避免,3040,例事件,未导致肾脏疾病的进展,肌病、肝胆疾病、癌症或非血管性死亡的风险未见增加,SHARP,研究提示的意义,慢性肾病患者进行降脂治疗提供循证医学证据,再次验证胆固醇理论：推论到整个动脉粥样硬化的预防当中，归根结底是胆固醇代谢的问题，只要用合适的方法降低了,LDL-C,，动脉粥样硬化事件风险就能下降,依折麦布联合辛伐他汀治疗的安全性值得肯定,更多医学精品尽在医学吧,