從全面降低心血管事件,逆轉(zhuǎn)粥樣斑塊,看聯(lián)合降脂ppt課件

1、1從全面降低心血管事件，逆轉(zhuǎn)粥樣斑塊看聯(lián)合降脂江蘇省中醫(yī)院神經(jīng)內(nèi)科吳明華2* 降低膽固醇的臨床必要性 -長(zhǎng)期降脂 強(qiáng)化降脂* 他汀局限性* 聯(lián)合降脂 IMPROVE-IT依折麥布聯(lián)合辛伐他汀進(jìn)一步降低心血管風(fēng)險(xiǎn) PRECISEIVUS依折麥布聯(lián)合他汀逆轉(zhuǎn)粥樣斑塊* 選擇性膽固醇吸收抑制劑臨床應(yīng)用中國(guó)專家共識(shí)（2015）目錄3血脂異常與CHD風(fēng)險(xiǎn)關(guān)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

2、Heart Disease. Circulation. 2015;131:451-458.)Years of Hyperlipidemia & CHD4無(wú)粥樣硬化人群不同的無(wú)粥樣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靈長(zhǎng)類動(dòng)物靈長(zhǎng)類動(dòng)物健康新生兒健康新生兒30-70mg/dL50-75mg/dL30mg/dL狩獵采集民狩獵采集民雜合子低雜合子低脂脂蛋白血癥患者蛋白血癥患者111mg/dL121mg/dL126mg/dL133mg/dL130mg/dL美國(guó)成人平均美國(guó)成人平均LDL-CForrester JS.

3、J Am Coll Cardiol 2010;56:6306.其中一組數(shù)據(jù)來(lái)自1988-1989年中國(guó)彝族農(nóng)村男性(平均年齡31歲)橫斷面調(diào)查，發(fā)現(xiàn)其LDL-C僅達(dá)到61mg/dlAm J Epidemiol 1996;144:839-48.5冠心病一級(jí)預(yù)防臨床研究冠心病一級(jí)預(yù)防臨床研究LDL-CLDL-C水平降至水平降至62mg/dl62mg/dl仍有臨床獲益仍有臨床獲益0LDL-C (mg/dL)CHD events (%)y=.0599x 3.3952R2=.9305P=.0019246810ASCOT-ATASCOT-PAFCAPS-PAFCAPS-LOWOSCOPS-PRWOSCOP

4、S-PCARDS-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安慰劑安慰劑Lancet 2009; 373: 11758

5、2LDL-C 62mg/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

6、 al. Am Heart 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冠心病二級(jí)預(yù)防臨床研究冠心病二級(jí)預(yù)防臨床研究LDL-CLDL-C水平降至水平降至54mg/dl54mg/dl仍有臨床獲益仍有臨床獲益7膽固醇理論8膽固醇理論CTT薈萃進(jìn)一步確立了膽固醇

7、理論1.LDL-C每降低1mmol/L，心血管事件降低約20%;2.他汀的心血管獲益主要是通過(guò)降低LDL-C獲得9指南推薦越來(lái)越嚴(yán)格的降脂目標(biāo)2013IAS血脂管理推薦：一級(jí)預(yù)防：LDL-C2.6mmol/L(100mg/dl)，非HDL-C3.4mmol/L(130mg/dl)二級(jí)預(yù)防：對(duì)于確診的ASCVD患者，LDL-C的最佳水平為1.8mmol/L(70mg/dl)或更低，單用他汀類藥物達(dá)標(biāo)時(shí)，可聯(lián)用第2種降膽固醇藥物，考慮聯(lián)合應(yīng)用依折麥布或膽汁酸鰲合劑 2013年AHA/ACC血脂管理推薦： 針對(duì)4類人群，直接啟動(dòng)高強(qiáng)度他汀。2015年NLA血脂管理推薦：提出“ the lower t

8、he better”,對(duì)于極高危患者LDL-C目標(biāo)值為70mg/dL。2014年CCEP專家建議：對(duì)于極高?；颊週DL-C目標(biāo)值為70mg/dL。10長(zhǎng)期降脂強(qiáng)化降脂11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.降降LDL-C局限性局限性劑量倍增，劑量倍增，LDL-C降幅僅僅增加降幅僅僅增加6%12要達(dá)到要達(dá)到50%50%的的LD

9、L-CLDL-C降幅降幅往往需要大劑量他汀往往需要大劑量他汀VOYAGER研究結(jié)果顯示：瑞舒伐他汀阿托伐他汀辛伐他汀5mg10mg20mg40mg10mg 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):69-76.13他汀局限性三項(xiàng)在中國(guó)冠心病患者強(qiáng)化與常規(guī)劑量他汀對(duì)比的臨床終點(diǎn)研究均為陰性結(jié)果CHILLAS研究：研究：中國(guó)ACS患者他汀劑

10、量的研究（開放、多中心）ISCAP研究：研究： PCI術(shù)前阿托伐他汀強(qiáng)化治療在中國(guó)擇期PCI干預(yù)冠心病患者中的應(yīng)用中韓中韓ALPACS研究研究:強(qiáng)化他汀在未接受他汀治療的NSTEACS患者中的應(yīng)用 14強(qiáng)化降脂強(qiáng)化降脂=目標(biāo)強(qiáng)化目標(biāo)強(qiáng)化強(qiáng)化降脂強(qiáng)化降脂大劑量他汀治療大劑量他汀治療聯(lián)合治療新選擇聯(lián)合治療新選擇15一項(xiàng)橫斷面調(diào)查研究的結(jié)果顯示15： 依折麥布聯(lián)合任意他汀均能獲得良好的依折麥布聯(lián)合任意他汀均能獲得良好的LDL-C降幅降幅亞洲人群數(shù)據(jù)：依折麥布與任意他亞洲人群數(shù)據(jù)：依折麥布與任意他汀聯(lián)合治療汀聯(lián)合治療LDL-CLDL-C降幅顯著增加降幅顯著增加15. Teramoto T, et al

11、. Current Therapeutic Research 2012;73:1-15.所有組與他汀單藥治療相比P 100mg/dL篩選不達(dá)標(biāo)患者篩選不達(dá)標(biāo)患者LDL-C 100mg/dLHarold E. Bays, American Journal of Cardiology. Sep 3, 2013, Published on line 聯(lián)合降脂高?；颊呤褂冒⑼蟹ニ〔贿_(dá)標(biāo)時(shí)，加用依折麥布與劑量加倍或換用瑞舒伐他汀的療效比較依折麥布/他汀VS他汀加倍17LDL-C降幅：加用依折麥布VS. 他汀劑量加倍或換用瑞舒伐他汀A10 E10+A10A10 A20A10 R10A20 E10+A20

12、A20 A40R10 E10+A20R10 R20第一階段第二階段-12.7*-9.1*-10.5*-9.5*Harold E. Bays, American Journal of Cardiology. Sep 3, 2013, Published on line *P79 mg/dL)Duration: 5,250 首發(fā)事件* 隨訪時(shí)間 2.5 yearsInclusion Criteria:Acute coronary syndrome (ACS)(UA, STEMI, NSTEMI)Baseline LDL-C:無(wú)降脂治療史: 50 mg/dL ( 1.3 mmol/L) and 12

13、5 mg/dL ( 3.2 mmol/L)之前接受過(guò)降脂治療者: 50 mg/dL ( 1.3 mmol/L) and 100 mg/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 (CV

14、A), and coronary revascularisation ( 30 days after randomisation)1,2Adapted 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-

15、ITIMPROVE-ITIMPROVE-ITmodified from: Cannon CP et al. American Heart Association (AHA) annual meeting 2014.隨即后的時(shí)間隨即后的時(shí)間(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 9,00

16、98,9218,3067,8437,2896,9396,6076,1925,6845,267 4,3953,3872,5691,068Patients at risk* median time averageSimvastatin 69.5 mg/dL*Ezetimibe/Simvastatin 53.7 mg/dL*依折麥布/辛伐他汀降低LDL-C分析降低降低LDL-C，依折麥布，依折麥布/辛伐他汀辛伐他汀vs辛伐他汀辛伐他汀21IMPROVE-ITIMPROVE-IT依折麥布/辛伐他汀全面降低血脂水平1年時(shí)的年時(shí)的平均值平均值LDL-CNon-HDL-cTCTGHDLhsCRPSimva6

17、9.997.1145.1137.148.13.8EZ/Simva53.277.2125.8120.448.73.3差值 mg/dL-16.719.9-19.3-16.7+0.6-0.5P value0.0010.0010.0010.0010.0010.001全面降低致動(dòng)脈粥樣硬化膽固醇及全面降低致動(dòng)脈粥樣硬化膽固醇及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事件發(fā)生率事件發(fā)生率(%)隨機(jī)后時(shí)間隨機(jī)

18、后時(shí)間(years)40302010001234567RRR: relative risk reduction for CV events; 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 201

19、5. DOI: 10.1056/NEJMoa1410489.IMPROVE-ITIMPROVE-IT首次主要終點(diǎn)事件：依折麥布/辛伐他汀vs.辛伐他汀首要終點(diǎn)：心血管死亡，心梗，因不穩(wěn)定心絞痛再次住院，隨機(jī)30天后冠脈血運(yùn)重建，或卒中依折麥布/辛伐他汀降低事件發(fā)生率23IMPROVE-ITIMPROVE-IT依折麥布/辛伐他汀解讀意義：1.豐富并再次驗(yàn)證了動(dòng)脈粥樣硬化之膽固醇學(xué)說(shuō) 膽固醇學(xué)說(shuō)再添新證據(jù) 吸收之膽固醇不僅與AS相關(guān)也與事件相關(guān) 他汀強(qiáng)化后的殘余心血管風(fēng)險(xiǎn)與LDL-C相關(guān) LDL-C在50-70mg/dL內(nèi)越低越好，為最低值提供參考2.論證了非他汀降LDL-c藥物也能減少CVE3.

20、建立了安全有效的強(qiáng)化調(diào)脂治療方法聯(lián)合降脂24逆轉(zhuǎn)粥樣斑塊CAD患者，冠脈照影或PCI史使LDL-C70mg/dLKenichi Tsujita, JACC，VOL.66, NO.5,2015PRECISE-IVUSPRECISE-IVUSPlaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound25逆轉(zhuǎn)粥樣斑塊首要指標(biāo)：PAV%（粥樣斑塊體積百分比絕對(duì)變化值）次要指標(biāo)：TAV normalized（歸一化總斑塊體積變化百分

21、比）其他實(shí)驗(yàn)室指標(biāo)：TC, LDL-C, TG, HDL-C, Lp(a), Lp(B)等 IVUS入組時(shí)，隨訪3個(gè)月，6個(gè)月，9個(gè)月時(shí)監(jiān)測(cè)Kenichi Tsujita, et al. JACC，VOL.66, NO.5,2015PRECISE-IVUSPRECISE-IVUS26PRECISE-IVUSPRECISE-IVUS黃色代表黃色代表聯(lián)聯(lián)合治合治療組療組， ，紅紅色色為單為單用阿托伐他汀治用阿托伐他汀治療組療組， ，聯(lián)聯(lián)合治合治療較單藥療較單藥治治療顯療顯著降低著降低LDL-C并并穩(wěn)穩(wěn)定定維維持至研究持至研究結(jié)結(jié)束束逆轉(zhuǎn)粥樣斑塊治療期間LDL-C變化27PRECISE-IVUSPR

22、ECISE-IVUS逆轉(zhuǎn)粥樣斑塊非劣性檢驗(yàn)PAV的絕對(duì)變化值依折麥布聯(lián)合阿托伐他汀vs阿托伐他汀 LZ組：組：依折麥布依折麥布+阿托伐他汀阿托伐他汀L組：組：阿托伐他汀阿托伐他汀28結(jié)果-主要終點(diǎn)指標(biāo)優(yōu)優(yōu)效性效性檢驗(yàn)結(jié)檢驗(yàn)結(jié)果果顯顯示，示，LZ組組主要主要終終點(diǎn)點(diǎn) PAV的的絕對(duì)絕對(duì)數(shù)數(shù)值變值變化化較較基基線線降低降低1.4%(3.4%0.1%) ， ，L組較組較基基線線降低降低0.3% (1.9%0.9%)， ，組間組間比比較較有有顯顯著差異著差異p 0.001 J Am Coll Cardiol. 2015;66(5):495-507. doi:10.1016/j.jacc.2015.05.065PRECISE-IVUSPRECISE-IVUS逆轉(zhuǎn)粥樣斑塊29結(jié)果-斑塊消退患者百分比P=0.004LZ組組冠脈斑冠脈