从全面降低心血管事件,逆转粥样斑块,看联合降脂20151022

1、从全面降低心血管事件，逆转粥样斑块看联合降脂江苏省中医院神经内科吴明华* 降低胆固醇的临床必要性 -长期降脂 强化降脂* 他汀局限性* 联合降脂 IMPROVE-IT依折麦布联合辛伐他汀进一步降低心血管风险 PRECISEIVUS依折麦布联合他汀逆转粥样斑块* 选择性胆固醇吸收抑制剂临床应用中国专家共识（2015）目录血脂异常与CHD风险关系11-20 yrs.(16.5%)1-10 yrs.(8.1%)0 yrs.(4.4%)Ann Marie，Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Hea

2、rt Disease. Circulation. 2015;131:451-458.)Years of Hyperlipidemia & CHD无粥样硬化人群不同的无粥样硬化人群不同的平均平均LDL-CLDL-C水平：水平：35-70mg/dl35-70mg/dl40-80mg/dL灵长类动物灵长类动物健康新生儿健康新生儿30-70mg/dL50-75mg/dL30mg/dL狩猎采集民狩猎采集民杂合子低杂合子低脂脂蛋白血症患者蛋白血症患者111mg/dL121mg/dL126mg/dL133mg/dL130mg/dL美国成人平均美国成人平均LDL-CForrester JS. J Am Col

3、l Cardiol 2010;56:6306.其中一组数据来自1988-1989年中国彝族农村男性(平均年龄31岁)横断面调查，发现其LDL-C仅达到61mg/dlAm J Epidemiol 1996;144:839-48.冠心病一级预防临床研究冠心病一级预防临床研究LDL-CLDL-C水平降至水平降至62mg/dl62mg/dl仍有临床获益仍有临床获益0LDL-C (mg/dL)CHD events (%)y=.0599x 3.3952R2=.9305P=.0019246810ASCOT-ATASCOT-PAFCAPS-PAFCAPS-LOWOSCOPS-PRWOSCOPS-PCARDS-

4、AT557595115135155175195CARDS-P阿托伐他汀阿托伐他汀普伐他汀普伐他汀瑞舒伐他汀瑞舒伐他汀洛伐他汀洛伐他汀Adapted from OKeefe JH et al. J Am Coll Cardiol. 2004;43:2142-2146; Colhoun HM et al. Lancet. 2004;364:685-696.AT=atorvastatin; LO=lovastatin; P=placebo; PR=pravastatin; RO=Rosuvastatin.JUPITER-RO安慰剂安慰剂Lancet 2009; 373: 117582LDL-C 62

5、mg/dlIMPROVE-IT EZE 54mg/dlAdapted from OKeefe JH et al. JACC 2004;43:2142-6P = placeboS = simvastatinPR = pravastatinAT = atorvastatinReferencesPROVE-IT: Cannon CP et al. N Engl J Med 2004; 350:1496-1504.IMPROVE-IT Background: Cannon CP et al. Am Heart J. 2008;156:826-832. 2. Califf RM, et al. Am H

6、eart J. 2010;159:705-709HPS: Lancet. 2003 Jun 14;361(9374):2005-16.CARE: N Engl J Med, 335 (1996), pp. 10011009LIPID: N Engl J Med. 1998; 339:1349-13574s: Lancet. 1994 Nov 19;344(8934):1383-9.62mg/dL冠心病二级预防临床研究冠心病二级预防临床研究LDL-CLDL-C水平降水平降至至54mg/dl54mg/dl仍有临床获益仍有临床获益胆固醇理论胆固醇理论CTT荟萃进一步确立了胆固醇理论1.LDL-C每降

7、低1mmol/L，心血管事件降低约20%;2.他汀的心血管获益主要是通过降低LDL-C获得指南推荐越来越严格的降脂目标2013IAS血脂管理推荐：一级预防：LDL-C2.6mmol/L(100mg/dl)，非HDL-C3.4mmol/L(130mg/dl)二级预防：对于确诊的ASCVD患者，LDL-C的最佳水平为1.8mmol/L(70mg/dl)或更低，单用他汀类药物达标时，可联用第2种降胆固醇药物，考虑联合应用依折麦布或胆汁酸鳌合剂 2013年AHA/ACC血脂管理推荐： 针对4类人群，直接启动高强度他汀。2015年NLA血脂管理推荐：提出“ the lower the better”,对

8、于极高危患者LDL-C目标值为70mg/dL。2014年CCEP专家建议：对于极高危患者LDL-C目标值为70mg/dL。长期降脂强化降脂他汀局限性LDL-C降幅（%）The rule of six. For each doubling of statin dose, only an additional 6% further lowering of low density lipoproteincholesterol is achieved.要达到要达到50%50%的的LDL-CLDL-C降幅降幅往往往往需要大剂量他汀需要大剂量他汀VOYAGER研究结果显示：瑞舒伐他汀阿托伐他汀辛伐他汀5m

9、g10mg20mg40mg10mg 20mg40mg80mg10mg 20mg40mg80mgn=670 n=11690 n=3554 n=2983n=7837 n=3908n=1324 n=2072N=165 n=2929 n=548 n=479Nicholls SJ, et al. Am J Cardiol. 2010;105(1):69-76.他汀局限性三项在中国冠心病患者强化与常规剂量他汀对比的临床终点研究均为阴性结果CHILLAS研究：研究：中国ACS患者他汀剂量的研究（开放、多中心）ISCAP研究：研究： PCI术前阿托伐他汀强化治疗在中国择期PCI干预冠心病患者中的应用中韩中韩A

10、LPACS研究研究:强化他汀在未接受他汀治疗的NSTEACS患者中的应用 联合治疗新选择联合治疗新选择一项横断面调查研究的结果显示15： 依折麦布联合任意他汀均能获得良好的依折麦布联合任意他汀均能获得良好的LDL-C降幅降幅亚洲人群数据：依折麦布与任意他亚洲人群数据：依折麦布与任意他汀联合治疗汀联合治疗LDL-C降幅显著增加降幅显著增加15. Teramoto T, et al. Current Therapeutic Research 2012;73:1-15.所有组与他汀单药治疗相比P 100mg/dL筛选不达标患者筛选不达标患者LDL-C 100mg/dLHarold E. Bays,

11、American Journal of Cardiology. Sep 3, 2013, Published on line 联合降脂高危患者使用阿托伐他汀不达标时，加用依折麦布与剂量加倍或换用瑞舒伐他汀的疗效比较依折麦布/他汀VS他汀加倍-22.2-9.5-13-17.4-6.9-17.1-7.5-25-20-15-10-50LDL-C降幅：加用依折麦布VS. 他汀剂量加倍或换用瑞舒伐他汀A10 E10+A10A10 A20A10 R10A20 E10+A20A20 A40R10 E10+A20R10 R20第一阶段第二阶段-12.7*-9.1*-10.5*-9.5*Harold E. Ba

12、ys, American Journal of Cardiology. Sep 3, 2013, Published on line *P79 mg/dL)Duration: 5,250 首发事件* 随访时间 2.5 yearsInclusion Criteria:Acute coronary syndrome (ACS)(UA, STEMI, NSTEMI)Baseline LDL-C:无降脂治疗史: 50 mg/dL ( 1.3 mmol/L) and 125 mg/dL ( 3.2 mmol/L)之前接受过降脂治疗者: 50 mg/dL ( 1.3 mmol/L) and 100 mg/

13、dL ( 2.6 mmol/L)40 mg Simvastatin(80 mg#, if LDL-C 79 mg/dL)*primary endpoint: composite of cardiovascular death (CVD) , non-fatal myocardial infarction (MI), hospital admission for unstable angina pectoris (UA), non-fatal stroke (CVA), and coronary revascularisation ( 30 days after randomisation)1,

14、2Adapted per FDA label of 2011: patients were no longere eligible for an increase in dose of simvastatin to 80 mg, and any patient who had beenreceiving the 80-mg dose for 1 year had the dose reduced to 40 mg.21 : 1IMPROVE-ITIMPROVE-ITIMPROVE-ITIMPROVE-ITmodified from: Cannon CP et al. American Hear

15、t Association (AHA) annual meeting 2014.随即后的时间随即后的时间(month)Mean LDL-C values (mg/dL)1009080706050400.5R14 48121624364860728496Ezetimibe/Simvastatin8,9908,8898,2307,7017,2646,8646,5836,2565,7345,3544,5083,4842,6081,078Simvastatin 9,0098,9218,3067,8437,2896,9396,6076,1925,6845,267 4,3953,3872,5691,068

16、Patients at risk* median time averageSimvastatin 69.5 mg/dL*Ezetimibe/Simvastatin 53.7 mg/dL*依折麦布/辛伐他汀降低LDL-C分析降低降低LDL-C，依折麦布，依折麦布/辛伐他汀辛伐他汀vs辛伐他汀辛伐他汀IMPROVE-ITIMPROVE-IT依折麦布/辛伐他汀全面降低血脂水平1年时的年时的平均值平均值LDL-CNon-HDL-cTCTGHDLhsCRPSimva69.997.1145.1137.148.13.8EZ/Simva53.277.2125.8120.448.73.3差值 mg/dL-16.

17、719.9-19.3-16.7+0.6-0.5P value0.0010.0010.0010.0010.0010.001全面降低致动脉粥样硬化胆固醇及全面降低致动脉粥样硬化胆固醇及TGTG水平水平Simvastatin 34.7% 2,742 events Ezetimibe/Simvastatin 32.7% 2,572 eventsHR 0.936 Cl (0.89;0.99) 7-year event rates事件发生率事件发生率(%)随机后时间随机后时间(years)40302010001234567RRR: relative risk reduction for CV events

18、; CV: cardiovascular; MI: myocardial infarction; UA: unstable angina pectoris; HR: Hazard Ratio; CI: confidence interval.RRR: 6.4%p = 0.016 Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489.IMPROVE-ITIMPROVE-IT首次主要终点事件：依折麦布/辛伐他汀v

19、s.辛伐他汀首要终点：心血管死亡，心梗，因不稳定心绞痛再次住院，随机30天后冠脉血运重建，或卒中依折麦布/辛伐他汀降低事件发生率IMPROVE-ITIMPROVE-IT依折麦布/辛伐他汀解读意义：1.丰富并再次验证了动脉粥样硬化之胆固醇学说 胆固醇学说再添新证据 吸收之胆固醇不仅与AS相关也与事件相关 他汀强化后的残余心血管风险与LDL-C相关 LDL-C在50-70mg/dL内越低越好，为最低值提供参考2.论证了非他汀降LDL-c药物也能减少CVE3.建立了安全有效的强化调脂治疗方法联合降脂逆转粥样斑块CAD患者，冠脉照影或PCI史使LDL-C70mg/dLKenichi Tsujita,

20、JACC，VOL.66, NO.5,2015PRECISE-IVUSPRECISE-IVUSPlaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound逆转粥样斑块首要指标：PAV%（粥样斑块体积百分比绝对变化值）次要指标：TAV normalized（归一化总斑块体积变化百分比）其他实验室指标：TC, LDL-C, TG, HDL-C, Lp(a), Lp(B)等 IVUS入组时，随访3个月，6个月，9个月时监测Kenic

21、hi Tsujita, et al. JACC，VOL.66, NO.5,2015PRECISE-IVUSPRECISE-IVUSPRECISE-IVUSPRECISE-IVUS黄色代表黄色代表联联合治合治疗组疗组， ，红红色色为单为单用阿托伐他汀治用阿托伐他汀治疗组疗组， ，联联合治合治疗较单药疗较单药治治疗显疗显著降低著降低LDL-C并并稳稳定定维维持至研究持至研究结结束束逆转粥样斑块治疗期间LDL-C变化PRECISE-IVUSPRECISE-IVUS逆转粥样斑块非劣性检验PAV的绝对变化值依折麦布联合阿托伐他汀vs阿托伐他汀 LZ组：组：依折麦布依折麦布+阿托伐他汀阿托伐他汀L组：组：阿托伐他汀阿托伐他汀结果-主要终点指标优优效性效性检验结检验结果果显显示，示，LZ组组主要主要终终点点 PAV的的绝对绝对数数值变值变化化较较基基线线降低降低1.4%(3.4%0.1%) ， ，L组较组较基基线线降低降低0.3% (1.9%0.9%)， ，组间组间比比较较有有显显著差异著差异p 0.001 J Am Coll Cardiol. 2015;66(5):495-507. doi:10.1016/j.jacc.2015.05.065PRECISE-IVUSPRECISE-IVUS逆转粥样斑块结果-斑块消退患者百分比P=0.004LZ