他汀藥物臨床應(yīng)用指南

1、他汀的指南與循證 臨床應(yīng)用的再思考,冠心病的分型,急性冠脈綜合癥（ACS） 不穩(wěn)定型心絞痛（UA） 非ST段抬高性心肌梗死（NSTEMI） ST段抬高性心肌梗死（STEMI） 冠心病猝死 慢性冠心病 穩(wěn)定型心絞痛 冠脈正常的心絞痛（如X-綜合征） 無癥狀性心肌缺血 缺血性心力衰竭（缺血性心肌?。?各型冠心病指南的危險分層與他汀/血脂治療原則,慢性穩(wěn)定性心絞痛診斷和治療指南,心絞痛嚴(yán)重度分級（參照加拿大心血管學(xué)會（CCS）心絞痛嚴(yán)重度分級） 危險分層可根據(jù)臨床評估，對負(fù)荷試驗的反應(yīng)，左心室功能及冠狀動脈造影顯示的病變情況綜合判斷,中華心血管病雜志2007年3月第35卷第3期,慢性穩(wěn)定性心絞痛診斷

2、和治療指南 他汀/血脂治療原則,改善預(yù)后的藥物治療建議（一） I類 所有冠心病穩(wěn)定性心絞痛患者接受他汀類藥物治療，LDL-C的目標(biāo)值2.60mmol/L（100mg/dl）（證據(jù)水平A） IIa類 有明確冠狀動脈疾病的極高?；颊撸晷难芩劳雎?%）接受強(qiáng)化他汀類藥物治療，LDL-C的目標(biāo)值2.07mmol/L（80mg/dl） （證據(jù)水平A） IIb類 糖尿病或代謝綜合癥合并低HDL-C和高甘油三酯血癥的患者接受貝特類或煙酸類藥物治療（證據(jù)水平B）,中華心血管病雜志2007年3月第35卷第3期,血脂不高的穩(wěn)定型心絞痛患者還需要服用他汀嗎？,LDL-C保持在100mg/dL以下，膽固醇不易流入

3、斑塊,粥樣病變體積百分比 (PAV) 的變化（）,病變進(jìn)展,-,1,-,0.5,0,0.5,1,1.5,2,50,60,70,80,90,100,110,120,A,-,Plus2,安慰劑,ACTIVATE1,安慰劑,CAMELOT4,安慰劑,REVERSAL5,普伐他汀,REVERSAL5,阿托伐他汀,病變減退,PERISCOPE=吡格列酮,JAMA. 2008;299(13):1561-73,LDL-C75mg/dL提示無斑塊進(jìn)展,P108(22):2757-62,不穩(wěn)定性心絞痛和非ST段抬高心肌梗死危險性分層,中華心血管病雜志2007年4月第35卷第4期,全球急性冠脈動脈事件注冊（GRA

4、CE）危險評分系統(tǒng),GRACE危險評分系統(tǒng) 低危患者（0-99分） 高?；颊撸?00）,中華心血管病雜志2007年4月第35卷第4期,不穩(wěn)定性心絞痛和非ST段抬高心肌梗死診斷與治療指南 他汀/血脂治療原則,他汀類藥物在ACS中的應(yīng)用 目前已有較多的證據(jù)(PROVE IT、A to Z、MIRACL等)顯示，在ACS早期給予他汀類藥物，可以改善預(yù)后，降低終點事件，這可能和他汀類藥物抗炎癥及穩(wěn)定斑塊作用有關(guān)。因此ACS患者應(yīng)在24 h內(nèi)檢查血脂，在出院前盡早給予較大劑量他汀類藥物。 出院后的藥物治療 改善預(yù)后：如阿司匹林、B受體阻滯劑、調(diào)脂藥物(特別是他汀類藥物)、ACEI(特別對LVEF040的

5、患者)、糖尿病等 ACS患者包括血管重建治療的患者，出院后應(yīng)堅持口服他汀類降脂藥物和控制飲食，LDL-C目標(biāo)值259 mmolL(100 mgm)，高危患者可將LDL-C降至207 mmolL(80 mgdn)以下 (證據(jù)水平A)。,中華心血管病雜志2007年4月第35卷第4期,？,2007 ACC AHA for UA and NSEMI,There is a wealth of evidence that cholesterol-lowering therapy for patients with CAD and hypercholesterolemia or with mild chol

6、esterol elevation (mean 209 to 218 mg per dL) after MI and UA reduces vascular events and death. Moreover, recent trials have provided mounting evidence that statin therapy is beneficial regardless of whether the baseline LDL-C level is elevated. More aggressive therapy has resulted in suppression o

7、r reversal of coronary atherosclerosis progression and lower cardiovascular event rates, although the impact on total mortality remains to be clearly established. These data are discussed more fully elsewhere.,ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevatio

8、n Myocardial Infarction。Journal of the American College of Cardiology Vol. 50, No. 7, 2007。,急性ST段抬高型心肌梗死診斷和治療指南,中華心血管病雜志2010年8月第38卷第8期,冠狀動脈及其他動脈硬化性血管病二級預(yù)防指南-2006 AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease,Furthermore, if it is no

9、t possible to attain LDL-C 70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of 50% with either statins or LDL-C lowering drug combinations. - LDL-C70mg/dl 或降幅50% Moreover, this guideline for patients with atherosclerotic disease does not modify the reco

10、mmendations of the 2004 ATP III update for patients without atherosclerotic disease who have diabetes or multiple risk factors and a 10-year risk level for CHD 20%. In the latter 2 types of high-risk patients, the recommended LDL-C goal of 100mg/dL has not changed.,2006 AHA/ACC Guidelines for Second

11、ary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease,NCEP Report. Circulation. 2004:110;227-39,2004 ATP III Update危險分層以及治療性生活方式改變和藥物治療的目標(biāo)值和切點,LDL-C水平與冠心病事件密切相關(guān) Lower is Better,Exp Opin Emerg Drugs 2004;9(2):269-79 N Engl J Med 2005;352:1425-35,中國成人血脂異常防治指南強(qiáng)調(diào)：嚴(yán)格分層治療，降低

12、心血管事件,中華心血管病雜志 2007;35(5):390-413,冠心病等危癥包括缺血性腦卒中、周圍動脈疾病、癥狀性頸動脈病、糖尿病等,慢性穩(wěn)定性心絞痛診斷和治療指南 他汀/血脂治療原則,改善預(yù)后的藥物治療建議（一） I類 所有冠心病穩(wěn)定性心絞痛患者接受他汀類藥物治療，LDL-C的目標(biāo)值2.60mmol/L（100mg/dl）（證據(jù)水平A） IIa類 有明確冠狀動脈疾病的極高?；颊撸晷难芩劳雎?%）接受強(qiáng)化他汀類藥物治療，LDL-C的目標(biāo)值2.07mmol/L（80mg/dl） （證據(jù)水平A） IIb類 糖尿病或代謝綜合癥合并低HDL-C和高甘油三酯血癥的患者接受貝特類或煙酸類藥物治療（

13、證據(jù)水平B）,中華心血管病雜志2007年3月第35卷第3期,ACC/ADA共同指出：血脂控制力度還需加大,對有心血管代謝危險因素和血脂異常的患者，推薦的治療目標(biāo)值：,其它主要CVD危險因素（血脂異常以外），包括：吸煙、高血壓、CAD早發(fā)的家族史,2009加拿大成人血脂異常及心血管疾病防治指南,高危患者的血脂管理不設(shè)起始值 膽固醇管理更積極：新增了LDL-C的降低幅度應(yīng)50%,2004 ATP III Update危險分層以及治療性生活方式改變和藥物治療的目標(biāo)值和切點,血脂指南仍阻礙了他汀的正確應(yīng)用？,定期查血，發(fā)現(xiàn)血脂異常 首選生活方式干預(yù)，改善血脂 血脂化驗單哪項異常，就選針對哪項異常的藥物

14、 血脂正?；蜻_(dá)標(biāo)后就減量或停藥 基線血脂水平正常就不需要調(diào)脂藥物 基線血脂水平偏低，就不能用降脂藥物,血脂治療現(xiàn)場直擊：,LDL-C目標(biāo)值？,2008年ACC/ADA共識：為防治動脈粥樣硬化,理論上所有人應(yīng)控制LDL-C在50mg/dL,JACC 2008;51(15):1512-1524,動物和人體的飲食和藥物干預(yù)試驗顯示，LDL-C降低的幅度與動脈粥樣硬化病變的穩(wěn)定和逆轉(zhuǎn)有關(guān)，這進(jìn)一步支持了LDL-C“低一點，好一些”的觀點，特別是在已經(jīng)明確CVD的患者中。 理論上，所有人都應(yīng)該將LDL-C維持在50mg/dL的“新生兒”水平，以預(yù)防動脈粥樣硬化，CVD患者也應(yīng)該控制在類似低的水平。,期待

15、2011 AHA，in Nov. at Orlando, USA!,不論基線血脂水平如何，他汀治療均顯著改善預(yù)后（Jupiter 亞組分析）,多個試驗納入標(biāo)準(zhǔn)沒有要求血脂異常,Asteroid研究：不設(shè)基線血脂水平，基線LDL-C130.4mg/dl；以20%管腔狹窄50%入排； Care研究：4159名，基線LDL-C139mg/dl，普伐他汀40mg治療5年，冠心病+平均血脂水平，心血管事件顯著減少； LIPID研究：冠心病血脂基本正常者長期使用他汀顯著減少嚴(yán)重不良心血管事件 。,他汀不僅僅是治療高脂血癥的降脂藥！ 他汀抗動脈粥樣硬化作用 多效性；穩(wěn)定/逆轉(zhuǎn)斑塊,而目前所有指南仍然強(qiáng)調(diào)10

16、0/70（80）。,在控制危險因素的基礎(chǔ)上控制動脈粥樣硬化,控制危險因素達(dá)標(biāo)（遵循指南） 管理AS,More Intensive Therapy Beginning in 2001, when we began to understand the implications of our findings published in 2002, we implemented in our clinic a change to treating arteries rather than simply treating risk factor levels. By 2003, this change

17、in approach had been fully implemented; the time required to implement the change was determined by the schedule of follow-up visits. Our approach to intensive therapy for accelerated atherosclerosis has previously been described. At baseline, therapy was intensified for those with a high plaque bur

18、den. During follow-up, therapy was intensified in patients in whom plaque was progressing despite treatment aimed at consensus targets for risk factors such as blood pressure and LDL cholesterol. This included using plaque measurements to motivate patients and to inform physicians about choices of m

19、edications,In patients with plaque progression, we increased the dose of statin to the maximum tolerated dose, regardless of LDL levels (eg, atorvastatin 80 mg or rosuvastatin 40 mg). In patients already at their maximum tolerated dose of statin, we added ezetimibe 10 mg daily. In those already usin

20、g the maximum dose of statin and ezetimibe, we added niacin for patients who were not diabetic or adding fibrates for diabetic patients or those unable to use niacin or slow-release niacin because of flushing.,J. David Spence, et. al. Stroke. 2010;41:00-00.),160mg/dl,54mg/dl,83mg/dl,55mg/dl,By excee

21、ding guideline-advocated treatment targets based on serial carotid plaque area measurement, we were able to reduce the proportion of patients with progression of plaque by half. This also reduced cardiovascular events. Among our patients with asymptomatic carotid stenosis, thecombined outcome of str

22、oke, death, myocardial infarction, or carotid endarterectomy (because of new cerebral symptoms on the side of the stenosis) declined from 17.6% before 2003 to 5.2% (P0.0001) since then. Carotid plaque burden assessed as TPA strongly predicted cardiovascular risk after adjusting for coronary risk fac

23、tors, and that plaque progression despite treatment according to guidelines further predicted cardiovascular risk.,J. David Spence, et. al. Stroke. 2010;41:00-00.),他汀的三級跨越 治療高脂血癥的降脂藥 兼顧LDL-C/HDL-C/TG的調(diào)脂藥 抗動脈粥樣硬化/防治心血管事件 的藥物 （抗AS領(lǐng)域的“青霉素”）,CVD高?；颊咧懈缓视腿ブ鞍缀虷DL-C:管理的證據(jù)與指導(dǎo),2011年4月29日，ESC發(fā)布的最新指南，強(qiáng)調(diào)對于LDL

24、-C達(dá)標(biāo)的CVD高?；颊?，應(yīng)強(qiáng)調(diào)富含甘油三酯脂蛋白(TRL)及HDL-C的管理的重要性；只有綜合調(diào)脂，才能進(jìn)一步降低事件風(fēng)險。,Chapman MJ, et al. European Heart Journal. doi:10.1093/eurheartj/ehr112,背 景,心血管疾病 CVD,降低LDL-C 降壓 預(yù)防血栓,生活方式干預(yù) 加藥物,當(dāng)前CVD的最佳治療,即使LDL-C達(dá)標(biāo)后，CVD高危患者的CVD事件風(fēng)險依然很高,TRL水平高和HDL-C水平低亦是CVD危險因素,Chapman MJ, et al. European Heart Journal. doi:10.1093/e

25、urheartj/ehr112,CV-1106-CR-0013,TRL和HDL-C的病理生理機(jī)制,TRL,HDL-C,穿過動脈內(nèi)膜，與結(jié)締組織基質(zhì)結(jié)合，并被巨噬細(xì)胞吞噬，形成泡沫細(xì)胞,促進(jìn)細(xì)胞內(nèi)膽固醇外流、抗炎及抗氧化作用,動脈粥樣硬化形成和發(fā)展,促,抗,Chapman MJ, et al. European Heart Journal. doi:10.1093/eurheartj/ehr112,CVD高危患者的血脂管理路徑,LDL-C水平達(dá)標(biāo)、伴TG1.7mmol/L和（或）HDL-C1.0mmol/L的CVD高危患者,強(qiáng)化生活方式干預(yù) 評估其他潛在病因 評估患者治療依從性,治療效果不佳，患

26、者血脂水平仍為TG1.7mmol/L和（或）HDL-C1.0mmol/L,強(qiáng)化降LDL-C治療，如在他汀類藥物基礎(chǔ)上加用依折麥布,考慮聯(lián)合應(yīng)用其他類調(diào)脂藥物，如煙酸類或貝特類藥物,Chapman MJ, et al. European Heart Journal. doi:10.1093/eurheartj/ehr112,CVD高?；颊叩难刂颇繕?biāo),Chapman MJ, et al. European Heart Journal. doi:10.1093/eurheartj/ehr112,Bonus! -其他強(qiáng)調(diào)他汀應(yīng)用的疾病指南,2010 ADA- Standards of Medica

27、l Care in Diabetes Dyslipidemia/lipid management Recommendations Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of n-3 fatty acids, viscous fiber, and plant stanols/sterols; weight loss (if indicated); and increased physical activity sh

28、ould be recommended to improve the lipid profile in patients with diabetes.(A) Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients: with overt CVD. (A) without CVD who are over the age of 40 years and have one or more other CVD risk factors

29、. (A) For patients at lower risk than described above (e.g., without overt CVD and under the age of 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains 100 mg/dl or in those with multiple CVD risk factors. (E),DIABETES CARE, VOLUME 33, SUPPLEMEN

30、T 1, JANUARY 2010,In individuals without overt CVD, the primary goal is an LDL cholesterol100 mg/dl (2.6 mmol/l). (A) In individuals with overt CVD, a lower LDL cholesterol goal of 70 mg/dl (1.8mmol/l), using a high dose of a statin, is an option. (B) If drug-treated patients do not reach the above

31、targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 3040% from baseline is an alternative therapeutic goal. (A),DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010,中國缺血性腦卒中和短暫性腦缺血發(fā)作二級預(yù)防指南2010,3脂代謝異常：膽固醇水平與缺血性腦卒中相關(guān)性較大。降低膽固醇水平主要通過行為生活方式改變和使用他汀類藥物。包括各種降脂治療(包括他汀類藥物、氯貝特、煙酸、膽汁酸

32、多價螫合劑、飲食)的大型薈萃分析顯示，只有他汀類藥物可以降低腦卒中的危險，他汀類藥物可以預(yù)防全身動脈粥樣硬化性病變的進(jìn)展，降低腦卒中復(fù)發(fā)風(fēng)險。 強(qiáng)化降低膽固醇預(yù)防腦卒中(Stroke Prevention by Aggressive Reduction in Cholesterol Levels，SPARCL)研究發(fā)現(xiàn)，強(qiáng)化他汀類藥物治療可顯著降低腦卒中和TIA的相對危險。盡管他汀類藥物治療組患者的出血性腦卒中有所增加，但致死性出血性腦卒中則沒有明顯增加。且作為一級預(yù)防的藥物，長期的他汀類藥物治療在心腦血管顯著獲益的同時并不顯著增加腦出血的風(fēng)險。對膽固醇水平升高的缺血性腦卒中和TIA患者，應(yīng)進(jìn)行生活方式干預(yù)、飲食及藥物治療，使用他汀類藥物治療使LDLC水平達(dá)到目標(biāo)值。對于肝腎功能正常的老年人，調(diào)脂藥物的劑量一般不需要特別調(diào)整，但對老年人的調(diào)脂治療要個體化，起始劑量不宜過大，應(yīng)予以嚴(yán)密監(jiān)測.,推薦意見：(1)膽固醇水平升高的缺血性腦卒中和TIA患者，應(yīng)該進(jìn)行生活方式的干預(yù)及藥物治療。建議使用他汀類藥物，目標(biāo)是使L