老年人血脂异常如何合理选择他汀.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,老年人血脂异常,-,如何合理选择他汀？,北京大学第一医院老年内科,刘梅林,治疗现状与心血管风险 老年高危患者他汀治疗率低下,JAMA.2004;291:1864-1870,年龄,66,岁，,39,万例,心血管疾病或糖尿病患者,处方他汀人数,8,万例,他汀处方率：,19%,老年人血脂异常防治现状,5000,名社区居住的,65,岁老年人随访研究：,1989,1990,年有,4.5%,有降脂治疗适应症的男性、,5.9%,的女性使用了降脂药物,1995,1996,年分别上升到,8.1%,、,10.0%,对老年人的高脂血症存在明显的治疗不足现象,达标以后停药现象非常普遍,解放军保健医学杂志,2004,年第,6,卷第,3,期,原因,老年人群较少进行全面检查；,对老年血脂异常未给予足够的关注；,药物的安全性顾虑,药物治疗的费用等,稳定性冠心病调脂治疗,二级预防临床试验,老年亚组分析，他汀类药物,降低全因死亡率,13%-34%,降低冠心病死亡率,18%-45%,减少主要冠脉事件,24%-34%,减少脑血管事件,12%-30%,老年人他汀二级预防荟萃分析,9,个临床试验（,4S,，,CARE,，,LIPID,，,HPS,，,PLACI,，,REGRESS,，,FLARE,，,LIPS,，,PROSPER,）,冠心病患者,19,569,例，,65-82,岁,每治疗,28,人挽救,1,人生命,(95%CI 15-56),J.Am.Coll.Cardiol.,2008;51;37-45,J Am Coll Cardiol 2008;51:3745,老年患者他汀治疗荟萃分析,（,9,个研究,19569,例患者）,p,均,0.05,他汀治疗稳定或逆转斑块,研究,研究人群,干预措施,检测手段,斑块改变,P,值,ATROCAP,1,颈动脉狭窄需颈动脉内膜剥脱术,阿托伐他汀,20mg/d,vs,安慰剂,组织化学分析,斑块表面溃疡、炎症反应减少,ESTABLISH,2,ACS,各,24,例,阿托伐他汀,20mg/d,vs,安慰剂,IVUS,-13.1,vs.,-8.7%,0.0001,REVERSAL,3,CHD,253,，,249,例,阿托伐他汀,80mg/d,Vs,普伐他汀,40mg/d,IVUS,-0.4%vs.,2.7%,0.02,ASAP,4,家族性高胆固醇血症,阿托伐他汀,80mg/d,Vs,辛伐他汀,40mg/d,CIMT,-0.031 mm vs,.,0.036 mm,0.0001,ARBITER,5,高胆固醇血症,阿托伐他汀,80mg/d,Vs,普伐他汀,40mg/d,CIMT,-0.034 mm vs,0.025 mm,0.03,ASTEROID,6,CHD,349,例,瑞舒伐他汀,40mg,自身对照,IVUS,-0.79%,（与基线比）,70,岁,辛伐他汀（,20-40mg/,天）,vs,阿托伐他汀（,80 mg/,天）,大剂量组,未获益，,更多副作用：,因肌痛、腹泻、腹痛和恶心中断治疗,（,9.6%vs 4.2%,，,p=0.001,）,ALT,明显升高,(1.0%vs 0.1%),老年人强化降脂治疗,稳定性冠心病,TNT,阿托伐他汀,10mg,或,80mg/,天,LDL-C,降至,2.6mmol/L,获益,老年人强化降脂治疗,稳定性冠心病,SAGE,阿托伐他汀,80mg/,天,vs,普伐他汀,40mg/,天,主要终点 缺血无差异,次要终点 降低死亡率,大剂量他汀安全性,肝功能,(AST,和,/,或,ALT3xULN),P0.001,P0.001,N Engl J Med 2005;352:1425-35.;JAMA.2005;294:2437-2445,0.18%,0.16%,1.20%,1.37%,0.00%,0.20%,0.40%,0.60%,0.80%,1.00%,1.20%,1.40%,1.60%,TNT,IDEAL,标准剂量,大剂量,大剂量他汀的耐受性,停药,N Engl J Med 2005;352:1425-35.;JAMA.2005;294:2437-2445,P0.001,P,安慰剂组,严重不良事件增加,肝酶升高发生率增加,A to Z,横纹肌溶解的发生率明显增加,一级预防试验,WOSCOPS,、,AFCAPS/TexCAPS,、,ASCOT-LLA,、,CHS,老年亚组分析他汀明显减少老年人心血管事件和死亡率,6575,岁的老年人从一级预防中终生获益,不是专为老年人设计，老年人的比例较低,JUPITER,大规模、前瞻性、安慰剂对照,17,802,例，瑞舒伐他汀组（,20mg/,日）和安慰剂组各,8901,例,平均年龄,66,（,60-71,）岁，中位随访时间,1.9,年,LDL-C 130 mg/dl(3.4 mmol/L),，平均,103 mg/dl(,2.8,mmol/L,),CRP,2.0 mg/L,，平均,4.2mg/L,JUPITER,Primary Trial Endpoint,:,MI,Stroke,UA/Revascularization,CV Death,Placebo 251/8901,Rosuvastatin 142/8901,HR 0.56,95%CI 0.46-0.69,P 0.00001,Number Needed to Treat(NNT,5,)=25,-44%,0,1,2,3,4,0.00,0.02,0.04,0.06,0.08,Cumulative Incidence,Follow-up(years),Ridker et al,NEJM 2008;359:2195-207,JUPITER,64(0.72%),143(1.6%),251(2.8%),安慰剂,*,48%(,21-66),p=0.002,33(0.37%),卒中,47%(30-60),76(0.85%),血运重建或不稳定心绞痛,44%(31-54),p=0.000001,1,42(1.6%),主要终点,HR,风险降低,(CI),瑞舒伐他汀,*,事件,*,N(%,随机化后,),.2,.4,.6,.8,1,1.2,瑞舒伐他汀更好,安慰剂更好,68(0.76%),54%(30-70),31(0.35%),所有,MI,157(1.8%),47%(30-61),83(0.93%),MI,卒中,CV,死亡,主要终点事件,：首次发生心血管死亡、心梗、卒中、不稳定心绞痛、动脉血管成形术,JUPITER,老年亚组,Primary endpoint,*,70 194 1.99 0.610.46-0.820.001,70 199 1.06 0.510.38-0.690.001,Any MI,70 47 0.50 0.550.31-1.000.046,70 52 0.30 0.370.21-0.690.001,Any stroke,70 61 0.64 0.550.33-0.930.023,70 36 0.20 0.450.22-0.910.020,Revascularisation or,70 87 0.95 0.510.33-0.800.003,Unstable Angina 70 132 0.69 0.540.38-0.770.001,MI/Stroke/CV Death,70 133 1.36 0.610.43-0.860.004,70 107 0.60 0.430.29-0.650.001,Secondary endpoints:,Any Death 70 241 2.04 0.800.62-1.040.090,70 204 0.86 0.800.60-1.050.10,VTE 70 40 0.41 0.590.31-1.110.096,70 54 0.28 0.550.31-0.960.031,Endpoint AgeEventsPlacebo rate,*,HR 95%CIP-value,*Incidence rates are per 100 person years;*Nonfatal MI,nonfatal stroke,revascularisation,unstable angina,CV death,HR Hazard Ratio;CI Confidence Interval,Treatment Effect by Age,Glynn RJ,Ridker PM.,www.escardio.org/congresses/esc-2009/congress-reports/Documents/710007-Glynn-slides.pdf,JUPITER,老年亚组,Any SAE,70 1,206 10.45 1.050.93-1.170.44,70 1,523 6.51 0.930.84-1.030.17,Muscle weakness,70 961 8.50 1.040.92-1.190.50,Stiffness or pain 70 1,835 7.85 1.040.94-1.130.46,Renal disorder,70 413 3.17 1.140.94-1.390.18,70 602 2.28 1.100.94-1.290.24,Hepatic disorder,70 120 0.95 1.010.71-1.450.95,70 282 0.99 1.240.98-1.570.07,Incident diabetes,70 146 1.03 1.250.90-1.740.18,95,50,98-99,95-98,90-98,88-90,可溶性,脂溶性,水溶性,脂,溶性,脂溶性,脂溶性,脂溶性,肾排泄（,%,）,10,20,6,13,5,95,90,肝脏代谢机制,CYP-450 3A4,硫化,CYP-450 2C9,CYP-450 3A4,CYP-450 3A4,CYP-450 2C9(10%),不同他汀类药物特点,特点,洛伐他汀,普伐他汀,氟伐他汀,辛伐他汀,阿托伐他汀,瑞舒伐他汀,清除半衰期,(,小时,),2-4,1-3,0.7-1.2,1-3,14,19,食物对吸收的影响,吸收,吸收,可忽略,无影响,无影响,无影响,服药的理想时间,早晚与食物同服,睡前,睡前,晚,晚,无要求,通过血脑屏障,是,否,否,是,否,否,活性代谢产物,有,无,无,有,无,无,生物利用度,(%),5,17,24,5,12,20,注意事项,肾功能不全时他汀血浓度可增高,经肝脏转换后，胆囊是他汀类的主要排泄途径,肝病患者服用时：低剂量,妊娠及孕妇不应服用,发生中枢系统副作用者，应选择不透过血脑屏障的他汀,他汀降低,LDL-C 30%-40%,所需剂量,(,标准剂量,)*,39-45,5-10,瑞舒伐他汀,25-35,40-80,氟伐他汀,35-41,20-40,辛伐他汀,34,40,普伐他汀,31,40,洛伐他汀,39,10,阿托伐他汀,LDL-C,降低（,%,）,剂量（,mg/d,）,药物,*LDL-C,降低数据来自各药说明书,他汀类对脂质和脂蛋白影响,-2535%,48,-55%,-42%,-2030%,48,-48%,-37%,-1525%,48,-41%,-32%,-1020%,48,-34%,-27%,-1015,48,-27,-22,TG,HDL-C,LDL-C,TC,氟伐他汀,脂质和脂蛋白的改变水平,80,80,40,80,40,20,80,40,40,20,10,40,20,20,10,普伐他汀,洛伐他汀,辛伐他汀,阿托伐他汀,他汀(,mg),LDL-C,自基线的改变,(%),0,10,20,30,40,50,60,10,mg*,5,15,25,35,45,55,20,mg,40,mg,10,mg,20,mg,80,mg,10,mg,20,mg,40,mg,80,mg,10,mg,20,mg,40,mg,瑞舒伐他汀 10,mg,46%,瑞舒伐他汀,阿托伐他汀,辛伐他汀,普伐他汀,40,mg,*,p0.001,与阿托伐他汀,10 mg;,辛伐他汀,10,20,40 mg;,普伐他汀,10,20,40 mg,相比,p0.002,与阿托伐他汀,20,40 mg;,辛伐他汀,20,40,80 mg;,普伐他汀,20,40 mg,相比,p0.001,与阿托伐他汀,40 mg;,辛伐他汀,40,80 mg;,普伐他汀,40 mg,相比,Am J Cardiol 2003;92:152-60,STELLAR,STELLAR,Am J Cardiol 2003;92:152-60,#,LDL-C,目标,100mg/dl,(,高危患者,),；,130,(,中危患者,),&,160,低危患者,)(,NCEP ATP III,标准,),*,P,0.002 与辛伐他汀,10mg,和,20mg;,普伐他汀,10mg,20mg,和,40mg,相比,P,=,0.00,7,瑞舒伐他仃,10mg,与,阿托伐他汀,1,0mg相比,0,20,40,60,80,100,n=,473,10mg,n=,473,20mg,n=,633,10mg,n=,633,20mg,n=,633,40mg,n=,633,80mg,n=,633,10mg,n=,633,20mg,n=,633,40mg,n=,633,80mg,n=,485,20mg,n=,485,40mg,n=,485,10mg,82%,89%,69%,75%,85%,82%,51%,63%,66%,82%,31%,44%,55%,*,LDL-C,达标,#,的患者,(%),瑞舒伐他汀,阿托伐他汀,辛伐他汀,普伐他汀,82%,患者达标,n=,473,40mg,瑞舒伐他汀,40mg,未在中国注册,89%,*,p0.002,与普伐他汀,10 mg,相比,p0.002,与阿托伐他汀,20,40,80 mg;,辛伐他汀,40 mg;,普伐他汀,20,40 mg,相比,p50%,CYP450 3A4,50%,CYP450 2D6,25%,CYP450 2C9,18%,细胞色素,P450,代谢药物,氟西汀（百优解）,舍曲林（左洛复）诺氟沙星,苯妥英钠,赛来考昔,大蒜,维拉帕米 奎尼丁,硝苯地平 华法林,、,吉非罗齐,、,那格列奈（唐力）,、,波生坦,、,格列苯脲,、,格列美脲,、,甲苯磺丁脲,氟伐他汀,瑞苏伐他汀,CYP450 2C9,伊曲康唑、奥美拉唑、环胞霉素,A,、大环内酯类抗生素,葡萄汁,胺碘酮、地高辛、氯吡格雷、氨氯地平、地尔硫卓、硝苯地平、异搏定、非洛地平、氯沙坦、厄贝沙坦、吉非罗奇、非诺贝特,阿托伐他汀,洛伐他汀,辛伐他汀,CYP450 3A4,其他,常用心血管药物,他汀,药物相互作用,ACC conference express 2005,J Am Coll Cardiol 2005:45(3.Suool A):382A.Abstract 1043-127,不同他汀对胺碘酮血药浓度的影响,*,CK,上升达,10,倍正常上限并有肌肉症状出现,发现,CK,正常上限,10,倍,的患者比例*,(%),0.0,0.5,1.0,1.5,2.0,2.5,3.0,20,30,40,50,60,70,LDL-C,的降低,(%),西立伐他汀,(0.2,0.3,0.4,0.8 mg),普伐他汀,(20,40 mg),阿托伐他汀,(10,20,40,80mg),辛伐他汀,(40,80mg),瑞舒伐他汀,(10,20,40 mg),Brewer HB Jr.Am J Cardiol.2003;92(4B):23K-29K.,他汀安全性,Brewer HB Jr.Am J Cardiol.2003;92(4B):23K-29K.,*,连续检测,2,次升高,正常上限的,3,倍,0.0,0.5,1.0,1.5,2.0,2.5,3.0,20,30,40,50,60,70,LDL-C,的降低,(%),发现,ALT,正常上限,3,倍,的患者比例,*,(%),氟伐他汀,(20,40,80mg),洛伐他汀,(20,40,80mg),阿托伐他汀,(10,20,40,80mg),辛伐他汀,(40,80mg),瑞舒伐他汀,(10,20,40 mg),他汀安全性,老年人调脂治疗,原则：积极谨慎,评估：,风险获益（,efficacy,risk,）,获益费用（,benefit,cost,）,最大的效益,-,风险比,选择哪种他汀,?,如果安全性相似,获益,/,费用比,多种药物合用时,选不同代谢途径药物,使用时间延长，他汀的获益增加,58,个临床试验,76,359,例他汀治疗,71,962,例对照,分别有,5440,和,7102,个事件,36,第六年及之后,33,第三到第五年,24,第二年,11,第一年,%,危险降低,试验中的年份,BMJ 2003;326:1423,停药对心梗后死亡率的影响,+82%,+96%,+186%,阿司匹林,倍他乐克,他汀,死亡率增加,Ho,P.M.et al.Arch Intern Med 2006;166:1842,5-Year NNT Values for Primary Prevention of CVD,JUPITER,WOSCOPS,AFCAPS/TexCAPS,HTN-Diuretics,HTN Beta Blockers,Aspirin-Men,Aspirin-Women,Number Needed to Treat(5 years),0,50,100,150,200,250,300,350,400,450,谢谢,