老年冠心病治療策略的演變

1、老年冠心病治療策略的演變The Strategic Changes of ElderlyCoronary Heart Disease Treatment,陳可冀 Chen Ke-ji 徐浩 Xu Hao中國中醫(yī)科學院西苑醫(yī)院心血管病中心衛(wèi)生部中日友好醫(yī)院全國中西醫(yī)結(jié)合心血管病中心 2008-05-23,2,老年冠心病臨床特點Clinical Features of Elderly CHD,嚴重心絞痛多/多支血管病變多

2、/復雜病變多/彌漫和鈣化病變多/陳舊心梗多/左室功能受累多/并存病多/無癥狀多/合并糖尿病多/嚴重心律失常多/病死率高 (高齡者三支病變>60%---TIME/APPROACH 試驗) (>75歲CHD發(fā)病率:男18.6%,女6.1%) (PCI,出血并發(fā)癥16.6%)治療目的:緩解癥狀/改善功能/提高生活質(zhì)量,3,冠心病治療觀念的改變Novel Changes in Concept of Elder

3、ly CHDTreatment,Luminal stenosis to vulnerable plaque formation 從重視管腔狹窄到易損斑塊 Lipid deposit to inflammatory response 從注意脂質(zhì)沉積到炎癥反應 Vulnerable plaque to vulnerable patient 從重視易損斑塊到易損病人Epicardial vessel open

4、 to myocardial perfusion　從注意心外膜冠脈開通到心肌組織水平灌注Outshine others to trio 從一枝獨秀到三駕馬車Single RF control to multi-RF intervention 從單一危險因素控制到多個危險因素聯(lián)合干預Standardized treatment to individualized therapy 從注重規(guī)范化治療到個體化治療

5、,4,Luminal Stenosis管腔狹窄,Vulnerable Plaque易損斑塊,,冠心病治療觀念改變之一First Change in Concept of CHD Treatment,5,Degree of Coronary Stenosis冠脈狹窄程度,Risk of CHD冠心病嚴重度,,動脈粥樣硬化的傳統(tǒng)觀念Traditional Concept of Atherosclerosis,?,6,急性心梗

6、前的冠脈狹窄程度Coronary Artery Stenosis pre-AMI,<50%,50-70%,>70%,% of Diameter Stenosis,% of the Patients,Bar graph shows severity of coronary artery stenosis before AMI (n=195, 4 studies) 68% patients had stenosis less

7、 than 50% at baseline86% patients had stenosis less than 70% at baselineFalk et al. Circulation. 1995;92:657.,7,降脂療法降低心臟事件但并不改變管腔狹窄Lipid-lowering Therapies Decrease Cardiac Events but Not Stenosis,,Levine GN, Keaney J

8、F Jr, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med.. 1995;332:512-521.Philbin EF, Pearson TA. How does lipid-lowering therapy rapidly reduce ischemic

9、events? J Myocard Ischemia.. 1994;6:13-18. Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park J-S, McGovern ME, for the PLAC I investigators. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): redu

10、ction in atherosclerosis progression and clinical events. J Am Coll Cardiol.. 1995;26:1133-1139,8,Coronary Artery Stenosis And Cardiac Events冠脈狹窄與心臟事件,Plaque volume or severity of coronary artery stenosis may not be the

11、 key factor for inducing cardiac events.提示:冠脈狹窄并非心血管事件關鍵原因,9,Concept of Vulnerable Plaque易損斑塊概念的提出,In 1989, Muller and colleagues first used “vulnerable plaques” to describe rupture-prone plaques as the underlying cau

12、se of most clinical coronary events. 首倡易損斑塊破裂觀念A vulnerable plaque often has a large lipid pool, a thin cap, and macrophage-dense inflammation on or beneath its surface. 特征Vulnerable plaque rupture or disruption cau

13、ses bleeding into the plaque, luminal thrombosis, and/or vasospasm that may cause sudden flow obstruction and ischemic injury. 破裂致血栓形成,Muller J, Tofler G, Stone P. Circadian variation and triggers of onset of acute cardi

14、ovascular disease. Circulation. 1989; 79:733–743.,,11,多方位策略演變 Many sided strategic changes,診斷進步：由以CAG為主導，到重視斑塊檢測技術(shù)的發(fā)展如IVUS、OCT；基礎研究方向：逐漸以穩(wěn)定易損斑塊以及減少斑塊破裂后血栓形成為方向；二級預防重點：也將由治療冠脈狹窄轉(zhuǎn)為易損斑塊的干預。,12,CHD develops in 20~30 years

15、 冠心病慢性病程Plaque rupture occurs in 2~3 hrs 斑塊破裂快過程,,Dyslipidemia,Atherosclerosis,Plaque formation,CHD,Heart failure,LV dysfunction,心臟事件的發(fā)生 Progression of Cardiac Events,AMI,LV reconstruction,13,冠脈介入治療的短處Limitations of

16、 PCI,Although PCI could relieve severe stenosis of coronary artery, it wouldn’t change the biologic course of AS, thus the problem of “unstable” is still unresolved. 尚未能解決斑塊不穩(wěn)定問題,14,COURAGE臨床試驗,Boden WE, et al. Opt

17、imal Medical Therapy with or without PCI for Stable coronary Disease (NEJM.356:1503-1516;April 12,2007),15,,,COURAGE –研究設計Study design of COURAGE trial,,,加PCI 組,不加PCI組,,,,,,死亡率/ MACE/ACS,,2287例穩(wěn)定型心絞痛患者( 他汀類, 抗血小板, ACEI

18、/ARB, β-受體阻滯劑),,,隨機化,,隨訪 2.5-7 Y,,16,兩組主要終點比較The comparison of endpoints with two groups,平均隨訪4.6年 所有原因死亡或非致死性心肌梗死數(shù) 單純優(yōu)化藥物治療組:18.5% 優(yōu)化藥物治療+PCI組:19.0% P=0.62,17,隨訪心絞痛緩解率Freedom from Angina During Long-Term Fo

19、llow-up,,The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.,18,震撼全球心血管病學界Grobal impact on cardiological field,

20、慢性穩(wěn)定性冠心病/臨界狹窄病變者:現(xiàn)代藥物治療效果理想/病人依從性好 COURAGE trial: 醫(yī)生應該有信心面對這些病人 保護病人效果和利益的最大化 在病人身上做有證據(jù)的治療 中西醫(yī)結(jié)合應受理解和提倡,19,兩組總生存率Overall Survival,Number at Risk,Medical Therapy 1138 1073 1

21、029917 717 468 302 38PCI 1149 1094 1051929 733 488 312 44,Years,0,1,2,3,4,5,6,0.0,0.5,0.6,0.7,0.8,0.9,1.0,PCI + OMT,OMT,7,,,,,,,,,,,,,,,,,,,,,,,,,,,,

22、,,,,,,,,Hazard ratio: 0.8795% CI (0.65-1.16)P = 0.38,20,穩(wěn)定易損斑塊的重要作用Stabilization of Vulnerable Plaques,The vascular pathophysiological research has focused on stabilizing the vulnerable plaque and inhibiting thrombosi

23、s after plaque rupture. The secondary prevention of CHD also focused on intervention of the vulnerable plaque in addition to treating luminal stenosis of coronary artery. 防治重點應是易損斑塊+狹窄問題,Kullo IJ, Edwards WD, Schw

24、artz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 1998; 129(12):1050-60. Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detection, treatment, and future implications. Curr Athero

25、scler Rep. 2005; 7(2):121-6,,21,Lipid Deposit脂質(zhì)沉積,Inflammatory Reaction炎癥反應,,冠心病治療觀念改變之二Second Change in Concept of CHD Treatment,22,逾百年之脂質(zhì)沉積學說Lipid Deposition Theory,“Lipid deposition theory” of atherosclerosis has

26、 been put forward for 150 years based on the causal relationship between hyperlipidemia and AS. 高脂血癥與動脈粥樣硬化關系This theory holds that lipid deposition on the artery wall leads to the AS plaques, and it has been domina

27、ted the pathogenesis of AS for a long time.,Steinberg D, Joseph L，Witztum JL. Lipoproteins and atherogenesis: Current concepts. JAMA 1990; 264(23):3047-3052.,,23,Inflammatory theory of AS was first presented by Virchow i

28、n 1856. 炎癥理論的提出“Endarteritis deformans” or atheroma - a product of an inflammatory process within the intima with the fibrous thickening evolved as a consequence of a reactive fibrosis induced by proliferating connectiv

29、e tissue cells within the intima.The theory did not raise great attention at that time. 當年未獲關注,動脈粥樣硬化炎癥學說Inflammation Theory,24,In recent years, AS was shown to have the basic manifestation of inflammation 炎癥反應的基本表現(xiàn)D

30、egenerationExudation ProliferationThe cell-cell interaction is similar to other chronic inflammation diseases such as rheumatoid arthritis, chronic pancreatitis and hepatic cirrhosis. AS was no longer regarded as a

31、simple disease of lipid deposition in the vessel wall, but also an advanced inflammatory reaction. In AS plaque of human, there was also evidence of several pathogens 病原Chlamydia pneumoniaeCytomegalovirusHerpes

32、virusHelicobacter pylori,動脈粥樣硬化炎癥學說Inflammation Theory,25,動脈粥樣硬化炎癥學說Inflammation Theory,In 1999, a century later, Ross declared that AS is one of chronic inflammatory disease, based on his injury reaction theory.損傷反應

33、理論的提出 (Ross,1999),26,動脈粥樣硬化的新概念The New Concept of AS,Traditional - “Rust in a pipe” (管腔生銹)Passive lipid deposition onto vessel wall,Current - “A fire within…” (管壁著火)Active inflammatory reaction inside vessel wall,27,

34、Inflammatory BiomarkersAS炎癥生物學標志物Inflammatory Biomarkers,白介素-6　　　　　?。梅磻鞍住　魏思毎吇蜃?1　血清淀粉樣蛋白Ａ腫瘤壞死因子α白介素-18白介素-10,細胞間黏附分子血管細胞黏附分子E-選擇素血管性假血友病因子,髓過氧化物酶磷脂酶血漿脂蛋白相關性磷脂酶,血管內(nèi)皮生長因子胎盤生長因子肝細胞生長因子,基質(zhì)金屬蛋白酶1

35、，2，9妊娠相關血漿蛋白-A,CD40配體P-選擇素,28,AS炎癥生物學標志物Hs-CRPC-Reactive Protein in CVD,Elevated hs-CRP levels in healthy populations predict vascular events such as MI and stroke as well as the development of diabetes. Hs-CRP is a

36、useful biomarker in risk prediction and treatment outcome assessment.Hs-CRP was also implicated directly in atherogenesis. CRP has been found in human atherosclerotic plaque and shown to cause endothelial cell dysfuncti

37、on, oxidant stress and intimal hypertrophy in experimental models.It could also be a potential target of AS treatment and prevention. 高敏C反應蛋白增高,Wilson AM, Ryan MC, Boyle AJ. The novel role of C-reactive protein in c

38、ardiovascular disease: risk marker or pathogen. Int J Cardiol. 2006; 106(3):291-7.,,29,基于幾種生化標記物的心血管事件相對風險,,,,,,0,1.0,2.0,4.0,6.0,,,Lipoprotein(a),,,LDLC,,,Homocysteine,,,TC,,,Apolipoprotein B,,,TC:HDLC,,,hs-CRP,,,hs-CRP

39、 + TC:HDLC,Relative Risk of Future CV Events,CV, cardiovascular; TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; HDL-C, high-density lipo-protein cholesterol; CRP, C-reative protein; hs-CRP, high-sensi

40、tivity C-reactive protein; TC, total cholesterol.Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.,30,hs-CRP (mg/L),,他汀治療6周對hs-CRP水平的影響The influence of Statins on hs-CRP level,Jialal I et al. Circulation 2001;103:

41、1933-1935.,6543210,Baseline,Prava(40 mg/d),Simva(20 mg/d),Atorva(10 mg/d),*p<0.025 vs. Baseline,31,ENHANCE試驗的啟示Enlightenment from ENHANCE trial,Kastelein,JJ.NEJM.April 3,2008;P.1431-1443,32,冠心病治療策略的更新Therap

42、eutic Strategies for CHD,Evidence based approach – Despite regulating blood lipid metabolism, statins should be recommended in its anti-inflammation and other protective effects on cardiovascular diseases. 推薦他汀藥物的應用

43、Anti-inflammation - several strategies that interfere with inflammation are in progress. 一些干予炎癥治療策略在發(fā)展中,Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detection, treatment, and future implications. Curr Ath

44、eroscler Rep. 2005; 7(2):121-6.,,33,Vulnerable Plaque易損斑塊,Vulnerable Patient易損病人,,冠心病治療觀念改變之三Third Change in Concept of CHD Treatment,34,易損病人概念的提出Definition of Vulnerable Patient,Vulnerable plaques are not the only

45、 culprit factors. Vulnerable blood and vulnerable myocardium play an important role in for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death.“Vulnerable patient" is propo

46、sed to define subjects susceptible to an acute coronary syndrome or sudden cardiac death based on plaque, blood, or myocardial vulnerability.Naghavi M. et al. Circulation 2003; 108(14):1664-72.,易損病人=易損斑塊+易損血液+易損心肌,35,,

47、A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables listed below.Vulnerable plaques 易損斑塊prone to rupture 易于破裂with high likelihood of thromboti

48、c complications and rapid progressionPlaque rupture accounts for nearly 70% of fatal AMI and/or sudden coronary deathsVulnerable plaque is the main, but not the unique cause for acute cardiovascular eventsVulnerable b

49、lood 易損血液prone to thrombosis 易于血栓形成Vulnerable myocardium 易損心肌prone to fatal arrhythmia 易發(fā)生致命性心律失常,易損病人Vulnerable Patient,36,治療上的創(chuàng)新性發(fā)展Development of Innovative Therapies,脂質(zhì)沉積 Lipid deposit,,調(diào)節(jié)血脂

50、 Regulating Blood Lipid,藥物: 擴冠 Drugs：Nitrates, CaA手術(shù) Surgery：PCI、CABG,,穩(wěn)定斑塊 Stabilizing Plaque, 抗炎 anti-inflammatory，抗栓(抗血小板、抗凝) Anti-thrombosis (anti-platelet,　anticoagulation),,,早期識別；重預防 Early Identificatio

51、n and Prevention,冠脈狹窄 Coronary Stenosis,,易損斑塊、破裂、血栓形成 Vulnerable Plaque, Rupture, Thrombosis,,易損患者 Vulnerable Patients,,37,血脂康——現(xiàn)代中藥Xuezhikang ——Modern Chinese Herbal Medici

52、ne,,Material: special produced red yeast rice原料：特制紅曲Method: red yeast rice (Oriza Sative L.) is grown on nutrient agar and special red yeast added, then fermented using modern biological technology to make the effecti

53、ve compound.方法：粳米加入培養(yǎng)液，接入特殊的紅曲霉菌種，運用現(xiàn)代生物技術(shù)發(fā)酵而成。,38,CARE vs. CCSPS,39,CCSPS亞組分析血脂康廣泛適用于特殊人群的調(diào)脂治療,合理·積極·謹慎老年人群高血壓人群糖尿病人群,40,日本MEGA STUDY結(jié)果表明: 東方人群溫和調(diào)脂即可明顯獲益,與CCSPS結(jié)果一致 MEGA Study’s result : similar to CC

54、SPS,對日本人的一級預防: 服用10-20mg的pravastatin可使冠心病危險↓33%; 與美歐用20-40mg效益相當對輕中度Tc增高的東方人群低劑量是安全有效的,Atheroscler Suppl. 2007 Aug;8(2):13-7. Epub 2007 Jun 22. LinksPrimary prevention of cardiovascular diseases among hypercho

55、lesterolemic Japanese with a low dose of pravastatin.Nakamura H; MEGA Study Group.,Tokyo, Japan - Results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, the fir

56、st large-scale primary-prevention trial in a Japanese population that showed statin therapy reduces the risk of coronary heart disease (CHD), have now been published in the September 30, 2006 issue of the Lancet. MEGA,

57、 first presented by lead author Dr Haruo Nakamura (National Defense Medical College, Saitama, Japan) at the American Heart Association Scientific (AHA) Sessions 2005 in Dallas, TX, showed that the addition of pravastatin

58、 10 mg to a low-fat diet rich in omega-3 fatty acids reduces the risk of CHD in Japanese individuals with moderately elevated cholesterol levels by 33%, approximately the same reduction observed in US and European primar

59、y-prevention trials that have used larger statin doses.,41,Platelets are inflammatory cells血小板實乃炎癥細胞,42,EBM 研究所得(Aspirin)Experience from EBM,43,抗血小板治療的困惑Certain puzzled problem on anti-platelet therapy,顱內(nèi)出血／胃腸道出血／鼻腔出

60、血／胸膜腔出血／皮下出血．．．（aspirin 75-100mg/d, clopidogril 75mg/d) 高齡尤多見; 遠超1.8-2.1％（CURE 研究）可適當減量（包括首劑負荷量）,44,Aspirin resistance概念的爭議,臨床Aspirin resistance : 減少事件/未能消除事件 AA基因多態(tài)性/無效或不利結(jié)果生化Aspirin resistance : 出血時間延

61、長/TXA2抑制合成/刺激血小板聚集 0.4-83.0% Dalen JE,et al:Am J Med,2007,120:1-4 Loordkipandize M,et al:Pharmaco Ther,2006,112:733-743,45,川芎嗪抗血小板作用Anti-platelet Effects of Ligustrazine,The active compon

62、ent of ABC herb--Ligusticum Chuanxiong 活血化瘀藥川芎主要成分Alkaloids 生物堿類 (Tetramethypyrazine, Ligustrazine)Lactones 內(nèi)酯類 四甲基吡嗪Phenols 酚性化合物Ferulic acid 阿魏酸Others 其它,46,活血藥抗TXA2生成Inhibitory Effect

63、s of ABC-herbs on TXA2 Production,,,芎芍膠囊干預治療研究XS0601 Reduces the Incidence of Restenosis Post-PCI (RIRE Trial, National Project),川芎有效部位 Paeoniflorin赤芍有效部位 Chuanxingol(國家十五攻關課題),,安貞醫(yī)院　同仁醫(yī)院　中日友好醫(yī)院　西苑醫(yī)院　廣東省中醫(yī)院,48,,,臨

64、床研究流程 Survey of Study,335 cases enrolled 335例入選,,Control group對照組 169 cases,,,Treatment group治療組 166 cases,308 cases completed with 147 repeat angiography 308例完成試驗，147例重復冠脈造影,,,Randomized隨機,

65、3 cases lost脫落,12 cases exclude剔除,3 cases lost脫落,9 cases exclude剔除,154 cases,154 cases,,,(47.4%),49,Comparison of clinical end-point event 兩組臨床終點事件的比較,Note: There was significant difference between the two

66、groups(p<0.05).,,,,,干預PCI術(shù)后再狹窄臨床結(jié)果比較,注: 兩組比較有顯著性差異(p<0.05).,50,□ XS0601Treatment▲Standard Treatment,P < 0.05,生存率比較XS0601 Improves Cumulative No-Event Survival,51,Integrative Medicine:The Experience from China

67、結(jié)合醫(yī)學經(jīng)驗：來自中國,52,Hs-CRP: Hypersensitive C-reaction Protein; MCP-1: Monocyte Chemoattractant Protein; TNF-α : Tumor Necrosis Factor-α,ABC+D藥物對炎癥指標變化比較Results: Inflammatory Marker Changes,53,老年冠心病治療多元模式Multiple Patterns f

68、or Elderly CHD Treatment,優(yōu)化藥物治療(證據(jù)和達標問題)PCI (Cypher/TAXUS,安全性/適應癥的長期考察)CABG (搭橋與藥物支架不能相互替代/在左主干和/或多支病變/或一支多處病變/鈣化比較嚴重的治療中有優(yōu)勢)心理干預多元模式互補,54,心外膜冠脈開通,心肌組織水平灌注,,冠心病治療觀念改變之四Fourth Change in Concept of CHD Treatment,55,