從全面降低心血管事件,逆轉(zhuǎn)粥樣斑塊,看聯(lián)合降脂20151022

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,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(zhuān)家共識(shí)（2015）,目錄,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 Heart Disease. Circulation. 2015;131:451-458.),Years of Hyperlipidemia & CHD,無(wú)粥樣硬化人群不同的平均LDL-C水平：35-70mg/dl,20-29歲,40-80mg/dL,靈長(zhǎng)類(lèi)動(dòng)物,健康新生兒,30-70mg/dL,50-75mg/dL,30mg/dL,狩獵采集民,雜合子低脂蛋白血癥患者,111mg/dL,30-39歲,40-49歲,60-69歲,121mg/dL,50-59歲,126mg/dL,133mg/dL,130mg/dL,美國(guó)成人平均LDL-C,Forrester JS. 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/dl,Am J Epidemiol 1996;144:839-48.,冠心病一級(jí)預(yù)防臨床研究LDL-C水平降至62mg/dl仍有臨床獲益,0,LDL-C (mg/dL),CHD events (%),y=.0599x 3.3952R2=.9305P=.0019,2,4,6,8,10,ASCOT-AT,ASCOT-P,AFCAPS-P,AFCAPS-LO,WOSCOPS-PR,WOSCOPS-P,CARDS-AT,55,75,95,115,135,155,175,195,CARDS-P,阿托伐他汀,普伐他汀,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,Lancet 2009; 373: 117582,LDL-C 62mg/dl,IMPROVE-IT EZE 54mg/dl,Adapted from OKeefe JH et al. JACC 2004;43:2142-6,P = placeboS = simvastatinPR = pravastatinAT = atorvastatin,ReferencesPROVE-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 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LDL-C水平降至54mg/dl仍有臨床獲益,膽固醇理論,膽固醇理論,CTT薈萃進(jìn)一步確立了膽固醇理論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,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(lèi)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(lèi)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 the better”,對(duì)于極高?；颊週DL-C目標(biāo)值為70mg/dL。,2014年CCEP專(zhuān)家建議：對(duì)于極高?；颊週DL-C目標(biāo)值為70mg/dL。,長(zhǎng)期降脂強(qiáng)化降脂,他汀局限性,The rule of six. For each doubling of statin dose, only an additional 6% further lowering of low density lipoproteincholesterol is achieved.,降LDL-C局限性劑量倍增，LDL-C降幅僅僅增加6%,要達(dá)到50%的LDL-C降幅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,5mg,10mg,20mg,40mg,10mg,20mg,40mg,80mg,10mg,20mg,40mg,80mg,n=670,n=11690,n=3554,n=2983,n=7837,n=3908,n=1324,n=2072,N=165,n=2929,n=548,n=479,Nicholls SJ, et al. Am J Cardiol. 2010;105(1):69-76.,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：中國(guó)ACS患者他汀劑量的研究（開(kāi)放、多中心）ISCAP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ALPACS研究:強(qiáng)化他汀在未接受他汀治療的NSTEACS患者中的應(yīng)用,強(qiáng)化降脂=目標(biāo)強(qiáng)化強(qiáng)化降脂大劑量他汀治療,聯(lián)合治療新選擇,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LDL-C降幅,亞洲人群數(shù)據(jù)：依折麥布與任意他汀聯(lián)合治療LDL-C降幅顯著增加,15. Teramoto T, et al. 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LDL-C 100mg/dL,Harold 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,LDL-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+A10,A10 A20,A10 R10,A20 E10+A20,A20 A40,R10 E10+A20,R10 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,*P2.5 years,Inclusion 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 125 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 (CVA), 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.2,1 : 1,IMPROVE-IT,IMPROVE-IT,modified from: Cannon CP et al. American Heart Association (AHA) annual meeting 2014.,隨即后的時(shí)間(month),Mean LDL-C values (mg/dL),100,90,80,70,60,50,40,0.5,R,1,4,4,8,12,16,24,36,48,60,72,84,96,Patients at risk,* median time average,Simvastatin 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LDL-C，依折麥布/辛伐他汀vs辛伐他汀,IMPROVE-IT,依折麥布/辛伐他汀全面降低血脂水平,全面降低致動(dòng)脈粥樣硬化膽固醇及TG水平,Simvastatin 34.7% 2,742 events,Ezetimibe/Simvastatin 32.7% 2,572 events,HR 0.936 Cl (0.89;0.99),7-year event rates,事件發(fā)生率(%),隨機(jī)后時(shí)間(years),40,30,20,10,0,0,1,2,3,4,5,6,7,RRR: 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 2015. DOI: 10.1056/NEJMoa1410489.,IMPROVE-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,IMPROVE-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.建立了安全有效的強(qiáng)化調(diào)脂治療方法聯(lián)合降脂,逆轉(zhuǎn)粥樣斑塊,CAD患者，冠脈照影或PCI史,使LDL-C70mg/dL,Kenichi Tsujita, JACC，VOL.66, NO.5,2015,PRECISE-IVUS,Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound,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.5,2015,PRECISE-IVUS,PRECISE-IVUS,黃色代表聯(lián)合治療組，紅色為單用阿托伐他汀治療組，聯(lián)合治療較單藥治療顯著降低LDL-C并穩(wěn)定維持至研究結(jié)束,逆轉(zhuǎn)粥樣斑塊,治療期間LDL-C變化,PRECISE-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：依折麥布+阿托伐他汀L組：阿托伐他汀,結(jié)果-主要終點(diǎn)指標(biāo),優(yōu)效性檢驗(yàn)結(jié)果顯示，LZ組主要終點(diǎn) PAV的絕對(duì)數(shù)值變化較基線降低1.4%(3.4%0.1%) ，L組較基線降低0.3% (1.9%0.9%)，組間比較有顯著差異p 0.001,J Am Coll Cardiol. 2015;66(5):495-507. doi:10.1016/j.jacc.2015.05.065,PRECISE-IVUS,逆轉(zhuǎn)粥樣斑塊,結(jié)果-斑塊消退患者百分比,P=0.004,LZ組冠脈斑塊消退的患者百分比顯著高于L組，78% VS 58%，P=0