调脂抗动脉粥样硬化的降ldlc与升课件

调脂抗动脉粥样硬化的 降LDL-C与升HDL-C LDL作为治疗目标的光辉时代 22.622.6 15.9/13.215.9/13.2 7.97.9 2.82.8 Placebo MI rate per 100 subjects per 5 yearsPlacebo MI rate per 100 subjects per 5 years WOS : NEJM 1995; 333 : 1301-1307 CARE : NEJM 1996; 335 : 1001-1009 LIPID : NEJM 1998; 339: 1349-1357 4S : Lancet 1994; 344 : 1383-1389 TexCAPS: JAMA 1998; 279: 1615-1622 他汀里程碑临床试验他汀里程碑临床试验 CARECARE n=4,159n=4,159 TC 5.4 TC 5.4 mmol/lmmol/l LIPIDLIPID n=9,014n=9,014 TC 5.6 TC 5.6 mmol/lmmol/l WOSWOS n=6,595 TC 7.0 n=6,595 TC 7.0 mmol/lmmol/l 4 4S S n=4,444n=4,444 TC 6.8 TC 6.8 mmol/lmmol/l With CHD +With CHD + high cholesterolhigh cholesterol With CHD +With CHD + normal cholesterolnormal cholesterol Without CHD +Without CHD + high cholesterolhigh cholesterol TexCAPSTexCAPS n=6,605 TC 5.7 n=6,605 TC 5.7 mmol/lmmol/l Without CHD + low HDL HPS: 低基线胆固醇水平病人也受益 40mg/d 20536 patients with CAD,hypertension,diabetes, PAD Cholesterol212mg/dl 随访期:3年 -24% RR p0.0001 -13% RR P=0.0003 -25% RR p0.0001 RR - relative reduction vs. placebo Adapted from HPS Collaborative Group, Lancet 2002;360:722 ASCOT: 主要终点(非致死心梗/致死冠心病) 0 1 2 3 4 0.00.51.01.52.02.53.03.5 Years Cumulative Incidence (%) 36% reduction HR = 0.64 (0.50-0.83) Atorvastatin 10 mgNumber of events100 PlaceboNumber of events 154 P = 0.0005 Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158 Hypertensives patients with other risk factors MIRACL: 主要疗效评定 Relative risk = 0.84 p=0.048 Atorvastatin Placebo 0 5 10 15 0481216 Time since randomization (weeks) Cumulative Incidence (%) Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence requiring urgent rehospitalization 17.4% 14.8% PROVE-IT:LDL-C中位数从基线的变化 (ACS后) Note: Changes in LDL-C may differ from prior trials: Note: Changes in LDL-C may differ from prior trials: 25% of patients on 25% of patients on statinsstatins prior to ACS event prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline LDL-C (mg/dL ) 20 40 60 80 100 120 Rand. 30 days 4 mos. 8 mos.16 mos. Final Pravastatin 40mg Atorvastatin 80mg 48% 48% 18%18% P0.001P0.001 Median LDL-C (Q1, Q3)Median LDL-C (Q1, Q3) 95 (79, 113)95 (79, 113) 62 (50, 79)62 (50, 79) 0 0 3 3 18182121242427273030 6 6 9 9 12121515 Months of Follow-up PravastatinPravastatin 40mg 40mg (26.3%)(26.3%) AtorvastatinAtorvastatin 80mg 80mg (22.4%)(22.4%) 16% RRR at 2 years16% RRR at 2 years (p = 0.005)(p = 0.005) 3030 2525 2020 1515 1010 5 5 0 0 PROVE-IT结果: 所有随机病人中全因死亡或重大心血管事件 % with% with Event Event ALLIANCE LDL-C initial LDL-C final Endpoint reduction (atorva vs usual care) Primary Secondary Atorvastat in 80mg/d (n=1217) 147mg/d l 95mg/ dl 17% 47% (p=0.02) (p=0.002) Usual care (n=1225) 147mg/d l 111mg/d l 设计不同的他汀研究 不同对象 老年人 PROSPER, FAME, SAGE 肾病病人 ALERT, 4D 糖尿病病人 ASPEN, CARDS 不同对照 安慰剂 不同他汀 同一他汀不同剂量 不同评价技术 血脂水平 冠脉造影 超声 IMT, IVUS 机制研究 降脂作用:主要作用 非降脂作用: 抗炎作用 治疗的目标水平是否越低越好治疗的目标水平是否越低越好? ? 来自 PROVE-I和REVERSAL的信息 The Lower Is Better低一些好一些 等待进一步被证实 TNT SEARCH IDEAL LDL-CLDL-C应降到多少低应降到多少低? ? 当前的指南都将当前的指南都将LDL-CLDL-C目标水平置于目标水平置于 100mg/dl. 100mg/dl. 现有的研究结果显示有可能将现有的研究结果显示有可能将 LDL-C LDL-C降至降至100100mg/mg/dLdL以下而取得更好结局以下而取得更好结局. . 指南可能要修订指南可能要修订, ,但但低到什么水平低到什么水平? ? 当前议题 他汀类是否应该用于广大人群中作一级预防他汀类是否应该用于广大人群中作一级预防? ? 英国英国: : 他汀按他汀按 OTC (OTC (非处方药非处方药) )供应或置于供应或置于 “ “PolypillPolypill”(”(多种药丸多种药丸) )内内 但有不同意见但有不同意见 Lancet Lancet 发表社论抨击以上做法发表社论抨击以上做法, ,认为认为 小剂量他汀用作一级预防缺少证据小剂量他汀用作一级预防缺少证据 其他国家其他国家: : 未有类似行动未有类似行动 当前议题 Editorial Lancet Volume 363, Number 9422，22 May 2004 OTC statins: a bad decision for public health From July, simvastatin will be available without a prescription in the UK. The Department of Health has accepted the advice of the Committee on Safety of Medicines (CSM) that simvastatin 10 mg can be sold through pharmacies to people at moderate risk of coronary heart disease. The UK is the first country to make a statin available over the counter (OTC). The decision followed a 10-week public consultation with 100 responses referred to the CSM. The reclassification summary concludes “The overall risk to benefit to the community of Pharmacy availability of Zocor Heart-Pro 10 mg tablets (simvastatin) is regarded as favourable“. Lets examine the facts. There are no trials of OTC statins for primary prevention of heart disease. There are no data on compliance with OTC statins, which for products that need to be taken daily longterm is a concern. Will those who buy simvastatin also stop smoking, lose weight, and do more exercise, or will they substitute drug use for lifestyle modification? Will pharmacists have the time to determine the individuals risk of coronary heart disease before selling the drug and also to give lifestyle advice? All these are unknowns, which is unfortunate for the UK public, who will be the guineapigs in this large-scale OTC experiment. Americans have escaped this role, with two applications for OTC statins (pravastatin 10 mg and lovastatin 10 mg) being rejected in 2000 because of insufficient evidence that either drug could be used safely and effectively in an OTC setting. 他汀是否再会有一次飞跃他汀是否再会有一次飞跃? ? 开发新的他汀开发新的他汀 不象很成功不象很成功, , 因为因为 在罗苏伐他汀和匹他伐他汀在罗苏伐他汀和匹他伐他汀( (PitavastatinPitavastatin) ) 之后无新的他汀研究信息之后无新的他汀研究信息 作为一个药的类别作为一个药的类别, ,受制于安全性受制于安全性. . 新近罗苏伐他汀制造商发出新近罗苏伐他汀制造商发出“ “致医师信致医师信” ” 联合治疗联合治疗 他汀他汀+贝特贝特 非诺贝特而不是吉非贝齐非诺贝特而不是吉非贝齐 他汀他汀+依泽替麦依泽替麦( (EzetimibeEzetimibe) ) 起始剂量他汀起始剂量他汀+依泽替麦降依泽替麦降LDL-CLDL-C幅度幅度 = = 最大可用剂量他汀最大可用剂量他汀 当前议题 Atorvastatin Ezetimibe + statin -70 -60 -50 -40 -30 -20 -10 0 Atorva 10 mg (n = 60) Atorva 20 mg (n = 60) Atorva 40 mg (n = 66) Atorva 80 mg (n = 62) Ezet + Atorva 10 mg (n = 65) Ezet + Atorva 20 mg (n = 62) Ezet + Atorva 40 mg (n = 65) Ezet + Atorva 80 mg (n = 63) Ezetimibe:与多种剂量阿托伐他汀合用对 LDL-C 的作用 -37% -53%* -42% -54%* -45% -56%* -54% -61%* *P 0.01 for ezetimibe + statin vs statin alone Mean Change in LDL-C From Untreated Baseline (%) Gagn C, et al. Am J Cardiol. 2002;90:1084-1091. Ezetimibe: 与多种剂量辛伐他汀合用对 LDL-C 的作用 Simvastatin Ezetimibe + statin -70 -60 -50 -40 -30 -20 -10 0 Simva 10 mg (n = 70) Simva 20 mg (n = 61) Simva 40 mg (n = 65) Simva 80 mg (n = 67) Ezet + Simva 10 mg (n = 67) Ezet + Simva 20 mg (n = 69) Ezet + Simva 40 mg (n = 73) Ezet + Simva 80 mg (n = 65) -27% -46%* -36% -46%* -38% -56%* -45% -58%* *P 0.01 for ezetimibe + statin vs statin alone Mean Change in LDL-C From Untreated Baseline (%) Gagn C, et al. Am J Cardiol. 2002;90:1084-1091. Ezetimibe: 与阿托伐他汀或辛伐他汀合用对甘油三酯和 HDL-C 的作用 Percent Change From Untreated Baseline All data are pooled across doses -40 -30 -20 -10 0 10 Atorvastatin Simvastatin Ezet + Statin Atorvastatin (n = 248)(n = 255) Simvastatin (n = 263) (n = 274) Atorvastatin (n = 248) (n = 255) Simvastatin (n = 263) (n = 274) -24% -33%* -20% -29%* 4% 7%*7% 9% TG (median)HDL-C (mean) *P 0.01 for ezetimibe + statin vs statin alone P 0.05 for ezetimibe + statin vs statin alone Gagn C, et al. Am J Cardiol. 2002;90:1084-1091. 如何将临床试验中得到的信息转化为临床实践？ 临床试验中为增大他汀类的防治能力，采用较大剂量的 较新他汀 关注大剂量他汀安全性 西立伐他汀事件 罗苏伐他汀致医师的信中也因为在一个国家发生多例严重 不良事件，建议起始用小剂量，逐步递增，但不超过批准的最高 剂量 从宏观上说，他汀类是安全的，但具体使用时应该是 谨慎的 他汀类对某些人群，如体重低、年老、多脏器病、肝肾功 能差、合并用药多者应特别小心 临床试验的大剂量在我国应用前先要有一个安全性试验 治疗初期认真监测肌酶和肝酶也十分重要 当前议题： 中国的降脂治疗空隙 我国血脂异常治疗现状的调查。中华心血管病杂志，2001.1 Vol.29, No.1 21%5% 只有5%的冠心病患者 血脂治疗达标 只有21%的糖尿病患者 血脂治疗达标 HDL-C 下一个调脂治疗的靶点 HPS enrolled high-risk primary- and secondary-prevention patients. HPS. Lancet. 2002;360:7. Downs. JAMA. 1998;279:1615. LIPID. N Engl J Med. 1998;339:1349. Sacks. N Engl J Med. 1996;335:1001. 4S. Lancet. 1995;345:1274. Shepherd. N Engl J Med. 1995;333:1301. % with CHD event Mean LDL-C level at follow-up (mg/dL) 0 5 10 15 20 25 30 90110130150170190210 CARE-Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI Secondary prevention Primary prevention WOSCOPS-PI WOSCOPS-Rx AFCAPS-Rx AFCAPS-PI HPS-Pl HPS-Rx HPS-Rx HPS-Pl w/revasc+ stroke CHD only PI=placebo Rx=treatment 70 LDL-C lowering is closely correlated with CV events reduction in trials HPS enrolled high-risk primary- and secondary-prevention patients. HPS. Lancet. 2002;360:7. Downs. JAMA. 1998;279:1615. LIPID. N Engl J Med. 1998;339:1349. Sacks. N Engl J Med. 1996;335:1001. 4S. Lancet. 1995;345:1274. Shepherd. N Engl J Med. 1995;333:1301. % with CHD event Mean LDL-C level at follow-up (mg/dL) 0 5 10 15 20 25 30 90110130150170190210 CARE-Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI Secondary prevention Primary prevention WOSCOPS-PI WOSCOPS-Rx AFCAPS-Rx AFCAPS-PI HPS-Pl HPS-Rx HPS-Rx HPS-Pl w/revasc+ stroke CHD only PI=placebo Rx=treatment 70 What should we do while LDL-C achieved 50mg/dL? 5050 寻找更多途径的原因 降LDL-C的效果可能有一定限度,现 有方法解决35%事件,其余? 已知糖尿病、代谢综合征、肥胖引起 的粥样硬化和冠心病以HDL-C低、 TG 高、LDL小而密为特征 如何升高HDL-C? 生活方式改变 减轻体重 戒烟 运动 饮食调节 总脂肪摄入 低脂肪饮食. 酒 总热卡限制 药物 烟酸:有用但有副作用，缓释剂好。 证据：HATS 贝特： 证据：VA-HIT 缓释烟酸的疗效缓释烟酸的疗效 Change from Baseline 2500 mg 3000 mg Goldberg A et al. Am J Cardiol 2000;85:1100-1105. 2000 mg 1500 mg 1000 mg 500m g HDL-C LDL-C Lp(a) TG 9% 14% 22% 21% 17% 29.5% 30% 26% 22% 15% 10% 28% 35% 44% 39% 11% 5% 26% 3% 12% 30% 24% 17% Change (%) Wolfe ML et al. Am J Cardiol 2001;87:476-479. Copyright 2001, Excerpta Medica Inc. Reprinted with permission. 因HDL-C持续低下而将缓释烟酸加与他汀之上 TCLDL-CHDL-CTG ApoA-1 Milano 故事 ApoA-1 Milano: 背景 意大利一小村中人HDL低但冠心病少,带有变型 的 ApoA-1 : ApoA-1 Milano 以有ApoA-1 Milano的血作动物试验证实有益 用重组的ApoA-1 Milano在ACS病人做预试验 Esperion Therapeutics 开发有效药物 ETC- 216 ApoA-1 Milano: 设计 57例ACS病人随机接受两种剂量的 ETC-216 (15 mg/kg or 45 mg/kg) 或安慰剂 用IVUS来估价粥样斑块变化，比较诊 断ACS两周内与 A-1 Milano治疗5周后 研究设计: 双盲，随机,安慰剂对照，多中心预试验，比 较静脉给重组 apo A-IMilano/磷脂复合物 (ETC-216) 或安慰剂对冠状动脉粥样斑块的作用，用血管内超声评价 (IVUS) 干预: 123 例病人筛选, 59例随机, 47哩完成方案l; 成 1:2:2,病人接受 5次每周一次滴注安慰剂或ETC- 216按15 mg/kg或45 mg/kg; 基线时和5周末作 IVUS检查粥样斑块 结果: 粥样斑块体积平均百分数变化： 联合ETC-216 组减少1.06% (p=.02); 粥样斑块绝对体积:在联合 ETC-216组为 14.1 mm3,或从基线降低 4.2% (p.001). 重组 Apo A-Imilano对ACS病人冠状动脉粥 样硬化的作用 Nissen SE et al. JAMA 2003;290:22922300. 基线血脂和粥样硬化 ETC-216 Placebo (n=12) 15 mg/kg (n=23) 45 mg/kg (n=22) LDL-C*118 25122 50112 32 HDL-C*46 738 1045 7 TG 212 153143 83150 77 Statin use4 (33%)9 (39%)12 (55%) IVUS Atheroma volume, %34.8 8.439.7 7.037.9 7.8 Total atheroma volume, mm3173 113296 167231 157 Mean maximum plaque thickness, mm0.65 0.320.82 0.190.74 0.28 Mean angiographic lumen diameter, mm2.28 0.632.41 0.422.37 0.34 * *Data from 4, 11, and 4 patients of the respective groupsData from 4, 11, and 4 patients of the respective groups Data from 10, 19, and 15 patients of the respective groupsData from 10, 19, and 15 patients of the respective groups Nissen SE et al. JAMA 2003;290:22922300. MeanMean Change from Baseline, % 重组 Apo A-IMilano (ETC-216)对粥样斑块 体积的百分数变化 *p=.03 0.140.14 Nissen SE et al. JAMA 2003;290:22922300. MedianMedian 1.291.29 0.730.73 1.061.06 0.030.03 1.141.14 * * 0.340.34 0.810.81 PlaceboPlacebo15 15 mg/kgmg/kg 45 mg/kg45 mg/kgCombineCombine d d p=.02 (1 endpoint) MeanMean Change from Baseline, mm3 重组 Apo A-IMilano (ETC-216)对粥样斑块 总体积的变化 *p=.02 2.92.9 Nissen SE et al. JAMA 2003;290:22922300. MedianMedian 15.115.1 12.612.6 14.114.1 0.20.2 15.015.0 * * 12.012.0 13.313.3 PlaceboPlacebo15 mg/kg15 mg/kg45 mg/kg45 mg/kgCombinedCombined p=.007 p.001 (2 endpoint) Different calculations of the primary end point in REVERSAL & ApoA-1 Milano Agent% change in total atheroma volume Pravastatin+2.7 Atorvastatin-0.4 ApoA-1 Milano-4.2 HDL: The key to regression? 在升高HDL方面有何发展? CETP 抑制剂( cholesteryl ester transfer protein) 介入胆固醇从HDL向LDL颗粒转