降脂治疗新趋势-从强化降脂走向全面调脂

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1、降脂治疗新趋势 从强化降脂走向全面调脂,降低LDL-C是调脂治疗的首要目标 降低LDL-C治疗显著降低了不同水平的总胆固醇水平 显著降低了心血管危险人群的冠心病发病率和死亡率 降低LDL-C不是调脂治疗的唯一目标 降低LDL-C仅使非致死性MI和死亡减少30% 使用他汀的患者仍可再发冠脉事件 全面调脂策略 降低LDL-C、TG、LP(a) + 升高HDL-C, 调脂治疗首要目标 强化降脂 降低LDL-C 他汀革命,Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators 4731

2、例无冠心病史的缺血性脑卒中或TIA的患者 首项通过降脂治疗对此类患者进行二级预防的前瞻性随机 双盲试验 结果:卒中后早期给予阿托伐他汀(80 mg/d)可使患者5年内 发生二次卒中的危险降低16% N Engl J Med 2006, 355(6): 549 (2006十大医学进展）,Vulnerable Plaque “ Active Volcano” Thrombotic effect ACS,Calcified Plaque “ Dormant Volcano ” Hemodynamic effect Stable Angina,2 Clinical Presentations of C

3、oronary Disease,Progression of Coronary Atheroma,Most AMI occurs with mildly stenotic plaques Fact or Fiction ?,Systemic Biomarkers for Plaque Inflammation,他汀*,LDL-C 下降,乳糜微粒和 VLDL残余, IDL, LDL-C的下降,恢复内皮功能 维护平滑肌细胞 抗炎作用 减少血栓形成,内腔,脂质核心,巨噬细胞,平滑肌细胞,ACS患者他汀治疗获益的原理,*关于以上4项作用和作用机理， 他汀之间有显著的差异。,血脂管理的进程,Adapte

4、d from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA1993;269:3015-3023; NCEP Expert Panel on Detection, Evaluation, and Treatment of High

5、Blood Cholesterol in Adults Arch Intern Med 1988;148:36-69.,只关注 LDL-C 的下降 强烈支持树脂和烟酸 他汀和菲诺贝特不作为一线用药,NCEP ATP I 1988,危险评估指导治疗 冠心病的LDL-C治疗目标 (2.6 mmol/L) 在高脂血症的治疗上, 他汀为 “主要药物,” 菲诺贝特为联合治疗,NCEP ATP II 1993,降LDL-C作为高危患者的起始治疗 冠心病等危症 LDL-C 降到2.6 mmol/L 降 LDL-C and TG作为治疗目标,NCEP ATP III 2001,Target 100 mg/dL

6、,NCEP ATP III : LDL-C Goals (2004 Updates),LDL-C level,* Therapeutic option in very high-risk patients and in patients with high TG, non-HDL-C100 mg/dL; * Therapeutic option; 70 mg/dL = 1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L,or optional 70 mg/dL*,100,70,13

7、0,160,190,High Risk,CHD or CHD risk equivalents ( 10-yr risk 20% ),Moderately High Risk, 2 risk factors ( 10-yr risk 10-20% ),Moderate Risk,Lower Risk, 2 risk factors ( 10-yr risk 10% ), 2 risk factors,Target 130 mg/dL,or optional 100 mg/dL*,Target 130 mg/dL,Target 160 mg/dL,Grundy SM et al. Circula

8、tion 2004; 110:227-239,强化降脂逆转动脉粥样硬化 REVERSAL,评价与普伐他汀(40mg/ d)比较,强化降脂(阿托伐他汀80mg/d)可否阻止或逆转冠状动脉斑块 用IVUS定量评估整个冠状动脉斑块总体积(TPV)在干预前后的18个月的变化百分率,REVERSAL,Nissen SE. JAMA. 2004;291: 1071-1080,REVERSAL,Nissen SE. JAMA. 2004;291: 1071-1080,与普伐他汀40mg组的斑块进展相比，立普妥80mg组的斑块进展显著减慢。 但与基线相比，斑块进展无显著差异。,舒降之治疗逆转冠状动脉粥样硬化-

9、 IVUS研究,用IVUS观察基线,3个月低脂饮食后,舒降之40mg进行再12个月治疗后 舒降之40mg，增加到80mg (如果1或3个月的40mg治疗不能使TC5.0mmol/dl、LDL-C3.0mmol/dl) “斑块+中膜”体积显著下降6.3% 舒降之40mg，LDL-C的降幅46.3%,Regression of Coronary Atherosclerosis by Simvastatin, A Serial Intravascular Ultrasound Study. Lisette O. Jensen, et al. Circulation 2004 110: 265-270

10、,脂谱变化,Regression of Coronary Atherosclerosis by Simvastatin, A Serial Intravascular Ultrasound Study. Lisette O. Jensen, et al. Circulation 2004 110: 265-270,舒降之 40mg, LDL-C在15个月后降幅: 46.3%,舒降之降脂治疗促使动脉粥样斑块逆转 (高分辨率,非侵入性MRI的2年随访)研究,21位无症状,未治疗的血脂异常患者, 通过超声或MRI确认的动脉粥样斑块(44个主动脉斑块, 32个颈动脉斑块), LDL-C130mg/dl

11、, 胸动脉斑块 4.0mm, 颈动脉斑块 2.0mm MRI观察舒降之40mg在基线和每6个月时患者的斑块变化, 共2年,Lipid Lowering by Simvastatin Induces Regression of Human Atherosclerotic Lesions. (Two Years Follow-Up by High-Resolution Noninvasive Magnetic Resonance Imaging) , Roberto Corti, MD. Circulation. 2002; 106: 2884-2887),P0.001,舒降之降脂治疗促使动脉粥样

12、斑块逆转 (高分辨率,非侵入性MRI的2年随访)研究,Circulation 2002; 106: 2884-2887,n=21,血浆脂质水平(mg/dl),时间（周） 血浆脂质水平时间变化折线图,TC,LDL-C,HDL-C,153例家族性高胆固醇血症的患者接受舒降之80mg治疗2年，观察颈动脉与股动脉IMT(内膜-中膜厚度)的变化,Arch Intern Med(163)1837-1841,-44.4%,ASAP的后续研究： 大剂量舒降之(80mg)的IMT消退研究,ASAP的后续研究： 大剂量舒降之(80mg)的IMT消退研究,P0.001,Pernette R et al.Arch I

13、ntern Med(163)1837-1841,P0.001,P0.001,舒降之治疗的重要性 因为AMI而实施过PCI的缺血性心衰患者,202名因AMI(左室射血分数40%)而实施过PCI的缺血性心衰患者 舒降之40mg (I 组) vs 非辛伐他汀 (II 组) 随访1年 心血管死亡下降 25% P=0.048 冠状动脉再狭窄率下降 60% P=0.033 再次PCI手术降低 60% P=0.033 显著改善左室射血分数,Prognostic Significance of Simvastatin Therapy in Patients with Ischemic Heart Failur

14、e Who Underwent Percutaneous Coronary Intervention for Acute Myocardial Infarction. The American Journal of Cardiology Vol. 95 March 1, 2005 619-622,舒降之20-40mg显著降低再次血运重建达37 显著降低冠脉死亡率42,4S,Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with co

15、ronary heart disease: The Scandinavian Simvastatin Survival Study(4S). Lancet 1994:344;1383-1389.,HPS,舒降之40mg可以显著降低所有血管再通术达24%, 显著降低冠脉死亡率达18%,Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: A randomi

16、zed placebo-controlled trial. Lancet 2002;360:7-22.,舒降之促进冠脉支架术患者的斑块逆转 IVUS随机研究,比较辛伐他汀20mg组与未治疗组 入选71名18-75岁，冠脉造影确定主冠状动脉狭窄率50%和择期进行血管再通术的患者 随访12个月 12个月后, 舒降之组支架外周斑块显著逆转，非支架处中间斑块显著逆转，主要危险事件显著减少,Simvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting: A randomized study with intravascular ultrasound; Am Heart Journ