老年冠心病治疗策略的演变

老年冠心病治疗策略的演变 The Strategic Changes of Elderly Coronary Heart Disease Treatment,陈可冀 Chen Ke-ji 徐浩 Xu Hao 中国中医科学院西苑医院心血管病中心 卫生部中日友好医院全国中西医结合心血管病中心 2008-05-23,2,老年冠心病临床特点 Clinical Features of Elderly CHD,严重心绞痛多/多支血管病变多/复杂病变多/弥漫和钙化病变多/陈旧心梗多/左室功能受累多/并存病多/无症状多/合并糖尿病多/严重心律失常多/病死率高 (高龄者三支病变60%-TIME/APPROACH 试验) (75岁CHD发病率:男18.6%,女6.1%) (PCI,出血并发症16.6%) 治疗目的:缓解症状/改善功能/提高生活质量,3,冠心病治疗观念的改变 Novel Changes in Concept of Elderly CHDTreatment,Luminal stenosis to vulnerable plaque formation 从重视管腔狭窄到易损斑块 Lipid deposit to inflammatory response 从注意脂质沉积到炎症反应 Vulnerable plaque to vulnerable patient 从重视易损斑块到易损病人 Epicardial vessel open to myocardial perfusion 从注意心外膜冠脉开通到心肌组织水平灌注 Outshine others to trio 从一枝独秀到三驾马车 Single RF control to multi-RF intervention 从单一危险因素控制到多个危险因素联合干预 Standardized treatment to individualized therapy 从注重规范化治疗到个体化治疗,4,Luminal Stenosis 管腔狭窄,Vulnerable Plaque 易损斑块,冠心病治疗观念改变之一 First Change in Concept of CHD Treatment,5,Degree of Coronary Stenosis 冠脉狭窄程度,Risk of CHD 冠心病严重度,动脉粥样硬化的传统观念 Traditional Concept of Atherosclerosis,?,6,急性心梗前的冠脉狭窄程度 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 than 50% at baseline 86% patients had stenosis less than 70% at baseline Falk et al. Circulation. 1995;92:657.,7,降脂疗法降低心脏事件但并不改变管腔狭窄 Lipid-lowering Therapies Decrease Cardiac Events but Not Stenosis,Levine GN, Keaney JF 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 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): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995;26:1133-1139,8,Coronary Artery Stenosis And Cardiac Events 冠脉狭窄与心脏事件,Plaque volume or severity of coronary artery stenosis may not be the key factor for inducing cardiac events. 提示:冠脉狭窄并非心血管事件关键原因,9,Concept of Vulnerable Plaque 易损斑块概念的提出,In 1989, Muller and colleagues first used “vulnerable plaques” to describe rupture-prone plaques as the underlying cause of most clinical coronary events. 首倡易损斑块破裂观念 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 causes 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 cardiovascular disease. Circulation. 1989; 79:733743.,11,多方位策略演变 Many sided strategic changes,诊断进步：由以CAG为主导，到重视斑块检测技术的发展如IVUS、OCT； 基础研究方向：逐渐以稳定易损斑块以及减少斑块破裂后血栓形成为方向； 二级预防重点：也将由治疗冠脉狭窄转为易损斑块的干预。,12,CHD develops in 2030 years 冠心病慢性病程 Plaque rupture occurs in 23 hrs 斑块破裂快过程,Dyslipidemia,Atherosclerosis,Plaque formation,CHD,ACS,Heart failure,LV dysfunction,心脏事件的发生 Progression of Cardiac Events,AMI,LV reconstruction,13,冠脉介入治疗的短处 Limitations of PCI,Although PCI could relieve severe stenosis of coronary artery, it wouldnt change the biologic course of AS, thus the problem of “unstable” is still unresolved. 尚未能解决斑块不稳定问题,14,COURAGE临床试验,Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable coronary Disease (NEJM.356:1503-1516;April 12,2007),15,COURAGE 研究设计 Study design of COURAGE trial,加PCI 组,不加PCI组,死亡率/ MACE/ACS,2287例稳定型心绞痛患者 ( 他汀类, 抗血小板, ACEI/ARB, -受体阻滞剂),随机化,随访 2.5-7 Y,16,两组主要终点比较 The comparison of endpoints with two groups,平均随访4.6年 所有原因死亡或非致死性心肌梗死数 单纯优化药物治疗组:18.5% 优化药物治疗+PCI组:19.0% P=0.62,17,随访心绞痛缓解率 Freedom from Angina During Long-Term Follow-up,The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P0.001) and 3 years (P=0.02) but not at baseline or 5 years.,18,震撼全球心血管病学界 Grobal impact on cardiological field,慢性稳定性冠心病/临界狭窄病变者:现代药物治疗效果理想/病人依从性好 COURAGE trial: 医生应该有信心面对这些病人 保护病人效果和利益的最大化 在病人身上做有证据的治疗 中西医结合应受理解和提倡,19,两组总生存率 Overall Survival,Number at Risk,Medical Therapy 1138 1073 1029 917 717 468 302 38 PCI 1149 1094 1051 929 733 488 312 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,Hazard ratio: 0.87 95% CI (0.65-1.16) P = 0.38,20,稳定易损斑块的重要作用 Stabilization of Vulnerable Plaques,The vascular pathophysiological research has focused on stabilizing the vulnerable plaque and inhibiting thrombosis 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. 防治重点应是易损斑块+狭窄问题,Kullo IJ, Edwards WD, Schwartz 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 Atheroscler Rep. 2005; 7(2):121-6,21,Lipid Deposit 脂质沉积,Inflammatory Reaction 炎症反应,冠心病治疗观念改变之二 Second Change in Concept of CHD Treatment,22,逾百年之脂质沉积学说 Lipid Deposition Theory,“Lipid deposition theory” of atherosclerosis has been put forward for 150 years based on the causal relationship between hyperlipidemia and AS. 高脂血症与动脉粥样硬化关系 This theory holds that lipid deposition on the artery wall leads to the AS plaques, and it has been dominated 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 in 1856. 炎症理论的提出 “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 connective tissue cells within the intima. The theory did not raise great attention at that time. 当年未获关注,动脉粥样硬化炎症学说 Inflammation Theory,24,In recent years, AS was shown to have the basic manifestation of inflammation 炎症反应的基本表现 Degeneration Exudation Proliferation The 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 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 pneumoniae Cytomegalovirus Herpes virus Helicobacter pylori,动脉粥样硬化炎症学说 Inflammation Theory,25,动脉粥样硬化炎症学说 Inflammation Theory,In 1999, a century later, Ross declared that AS is one of chronic inflammatory disease, based on his injury reaction theory. 损伤反应理论的提出 (Ross,1999),26,动脉粥样硬化的新概念 The New Concept of AS,Traditional - “Rust in a pipe” (管腔生锈) Passive lipid deposition onto vessel wall,Current - “A fire within” (管壁着火) Active inflammatory reaction inside vessel wall,27,Inflammatory Biomarkers AS炎症生物学标志物 Inflammatory Biomarkers,白介素-6 反应蛋白 单核细胞趋化因子-1 血清淀粉样蛋白 肿瘤坏死因子 白介素-18 白介素-10,细胞间黏附分子 血管细胞黏附分子 E-选择素 血管性假血友病因子,髓过氧化物酶 磷脂酶 血浆脂蛋白相关性磷脂酶,血管内皮生长因子 胎盘生长因子 肝细胞生长因子,基质金属蛋白酶 1，2，9 妊娠相关血浆蛋白-A,CD40配体 P-选择素,28,AS炎症生物学标志物Hs-CRP C-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 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 dysfunction, oxidant stress and intimal hypertrophy in experimental models. It could also be a potential target of AS treatment and prevention. 高敏C反应蛋白增高,Wilson AM, Ryan MC, Boyle AJ. The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen. Int J Cardiol. 2006; 106(3):291-7.,29,基于几种生化标记物的心血管事件相对风险,0,1.0,2.0,4.0,6.0,Lipoprotein(a),LDLC,Homocysteine,TC,Apolipoprotein B,TC:HDLC,hs-CRP,hs-CRP + 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-sensitivity C-reactive protein; TC, total cholesterol. Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.,30,hs-CRP (mg/L),他汀治疗6周对hs-CRP水平的影响 The influence of Statins on hs-CRP level,Jialal I et al. Circulation 2001;103:1933-1935.,6 5 4 3 2 1 0,Baseline,Prava (40 mg/d),Simva (20 mg/d),Atorva (10 mg/d),*p0.025 vs. Baseline,31,ENHANCE试验的启示 Enlightenment from ENHANCE trial,Kastelein,JJ.NEJM.April 3,2008;P.1431-1443,32,冠心病治疗策略的更新 Therapeutic 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. 推荐他汀药物的应用 Anti-inflammation - several strategies that interfere with inflammation are in progress. 一些干予炎症治疗策略在发展中,Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detection, treatment, and future implications. Curr Atheroscler Rep. 2005; 7(2):121-6.,33,Vulnerable Plaque 易损斑块,Vulnerable Patient 易损病人,冠心病治疗观念改变之三 Third Change in Concept of CHD Treatment,34,易损病人概念的提出 Definition of Vulnerable Patient,Vulnerable plaques are not the only 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 proposed 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.,易损病人=易损斑块+易损血液+易损心肌,35,A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables listed below. Vulnerable plaques 易损斑块 prone to rupture 易于破裂 with high likelihood of thrombotic complications and rapid progression Plaque rupture accounts for nearly 70% of fatal AMI and/or sudden coronary deaths Vulnerable plaque is the main, but not the unique cause for acute cardiovascular events Vulnerable blood 易损血液 prone to thrombosis 易于血栓形成 Vulnerable myocardium 易损心肌 prone to fatal arrhythmia 易发生致命性心律失常,易损病人 Vulnerable Patient,36,治疗上的创新性发展 Development of Innovative Therapies,脂质沉积 Lipid deposit,调节血脂 Regulating Blood Lipid,药物: 扩冠 Drugs：Nitrates, CaA 手术 Surgery：PCI、CABG,稳定斑块 Stabilizing Plaque, 抗炎 anti-inflammatory，抗栓(抗血小板、抗凝) Anti-thrombosis (anti-platelet, anticoagulation),早期识别；重预防 Early Identification and Prevention,冠脉狭窄 Coronary Stenosis,易损斑块、破裂、血栓形成 Vulnerable Plaque, Rupture, Thrombosis,易损患者 Vulnerable Patients,37,血脂康现代中药 Xuezhikang Modern Chinese Herbal Medicine,Material: special produced red yeast rice 原料：特制红曲 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 effective compound. 方法：粳米加入培养液，接入特殊的红曲霉菌种，运用现代生物技术发酵而成。,38,CARE vs. CCSPS,39,CCSPS亚组分析 血脂康广泛适用于特殊人群的调脂治疗,合理积极谨慎 老年人群 高血压人群 糖尿病人群,40,日本MEGA STUDY结果表明: 东方人群温和调脂即可明显获益,与CCSPS结果一致 MEGA Studys result : similar to CCSPS,对日本人的一级预防: 服用10-20mg的pravastatin可使冠心病危险33%; 与美欧用20-40mg效益相当 对轻中度Tc增高的东方人群低剂量是安全有效的,Atheroscler Suppl. 2007 Aug;8(2):13-7. Epub 2007 Jun 22. Links Primary prevention of cardiovascular diseases among hypercholesterolemic 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 first 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, 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 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 primary-prevention trials that have used larger statin doses.,41,Platelets are inflammatory cells 血小板实乃炎症细胞,42,EBM 研究所得(Aspirin) Experience from EBM,43,抗血小板治疗的困惑 Certain puzzled problem on anti-platelet therapy,颅内出血胃肠道出血鼻腔出血胸膜腔出血皮下出血（aspirin 75-100mg/d, clopidogril 75mg/d) 高龄尤多见; 远超1.8-2.1（CURE 研究） 可适当减量（包括首剂负荷量）,44,Aspirin resistance概念的争议,临床Aspirin resistance : 减少事件/未能消除事件 AA基因多态性/无效或不利结果 生化Aspirin resistance : 出血时间延长/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 component of ABC herb-Ligusticum Chuanxiong 活血化瘀药川芎主要成分 Alkaloids 生物碱类 (Tetramethypyrazine, Ligustrazine) Lactones 内酯类 四甲基吡嗪 Phenols 酚性化合物 Ferulic acid 阿魏酸 Others 其它,46,活血药抗TXA2生成 Inhibitory Effects of ABC-herbs on TXA2 Production,芎芍胶囊干预治疗研究 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 (国家十五攻关课题),安贞医院 同仁医院 中日友好医院 西苑医院 广东省中医院,48,临床研究流程 Survey of Study,335 cases enrolled 335例入选,Control group 对照组 169 cases,Treatment group 治疗组 166 cases,308 cases completed with 147 repeat angiography 308例完成试验，147例重复冠脉造影,Randomized 随机,3 cases lost脱落,12 cases exclude剔除,3 cases lost脱落,9 cases exclude剔除,154 cases,154 cases,(47.4%),49,Comparison of clinical end-point event 两组临床终点事件的比较,Note: There was significant difference between the two groups(p0.05).,干预PCI术后再狭窄临床结果比较,注: 两组比较有显著性差异(p0.05).,50, XS0601Treatment Standard Treatment,P 0.05,生存率比较 XS0601 Improves Cumulative No-Event Survival,51,Integrative Medicine:The Experience from China 结合医学经验：来自中国,52,Hs-CRP: Hypersensitive C-reaction Protein; MCP-1: Monocyte Chemoattractant Protein; TNF- : Tumor Necrosis Factor-,ABC+D药物对炎症指标变化比较 Results: Inflammatory Marker Changes,53,老年冠心病治疗多元模式 Multiple Patterns for Elderly CHD Treatment,优化药物治疗(证据和达标问题) PCI (Cypher/TAXUS,安全性/适应症的长期考察) CABG (搭桥与药物支架不能相互替代/在左主干和/或多支病变/或一支多处病变/钙化比较严重的治疗中有优势) 心理干预 多元模式互补,54,心外膜 冠脉开通,心肌组织水平 灌注,冠心病治疗观念改变之四 Fourth Change in Concept of CHD Treatment,55,再灌注治疗是AMI治疗的里程碑，从被动、保守转为主动、积极的血运重建，挽救了无数患者的生命 但临床发现， 约10-30%患者PCI成功后，心肌组织水平无再灌注，即无复流现象 无复流是PCI后死亡和心梗的独立预测因素,无复流现象的反思 Asking in reply on no-flow,Frederic SR, et al. Am Heart J 2003;145:42-46.,56,可能的机制 Possible mechanism,可能的机制 微血管结构完整性破坏 微栓子栓塞 白细胞聚集 微血管功能完整性损伤，主要是痉挛所致 血小板激活 氧自由基,57,策略演变 Strategic change,回顾再灌注历史：过去20年基本上是心外膜冠状动脉再灌注的20年，相信未来的10年将是微循环灌注的10年 检测手段： 冠脉微循环灌注评价：心肌声学造影成为热点 防治手段： 无复流防治：腺苷、CaA，活血化瘀中药等 微循环改善剂：未来冠心病研究方向之一？,Diabetes Care 29:202206, 2006,Circ J 2006; 70: 1099 1104),58,一枝独秀,三驾马车,冠心病治疗观念改变之五 Fifth Change in Concept of CHD Treatment,59,“药物支架时代”来临？ The trend of the DES times?,DES的出现，使心血管介入技术向前迈进了一大步，成为冠心病介入治疗的第3个里程碑。 BMS、冠脉搭桥术 以及传统药物治疗是 否真的要淡出舞台 ,60,Stenting (including drug-eluting stents) reduces restenosis and repeated intervention, but does not reduce mortality or myocardial infarction. 支架不降低心脏病死率或心梗,Serruys PW, Kutryk MJB, Ong ATL. Coronary-artery stents. N Engl J Med 2006;354:483-495.,61,FDA 05/12/2006 : 药物支架要求一万例验证三年,FDA: Heart patients with drug-coated stents face blood-clot risk By Associated Press Tuesday, December 5, 2006 WASHINGTON - Patients implanted with drug-coated stents to hold open their choked arteries face a small but significant risk of blood clots, health officials said Tuesday, and a new study recommended they take clot-busting medications indefinitely. Growing concerns about the long-term safety of drug-coated stents comes to a head this week, when the Food and Drug Administration convenes a two-day meeting to discuss clotting risks associated with the devices. In documents released Tuesday, the FDA said it is unknown whether there is an increased risk of death or heart attack in patients fitted with the so-called drug-eluting stents. However, those patients do face an increased risk of blood clots a year or more after surgery compared with those fitted with bare-metal stents, the agency said in citing recent studies. Natick, Mass.-based Boston Scientific Corp. and New Brunswick, N.J.-based Johnson & Johnson are the only two companies approved to sell the drug-coated versions. The FDA is seeking advice on a wide range of questions on the popular stents, including whether to update their labels with new warnings, identify patients for whom they arent appropriate and perhaps change federal recommendations on how long people should take blood thinners like Plavix and aspirin following stent surgery.,62,Stent vs CABG,国际上正在组织三个大规模随机对照临床研究进行多支血管病的DES和CABG疗效评估，相信这些研究将有助于明确二者各自的优势和适应证。 FREDOOM:多支血管病合并糖尿病患者的DES和CABG的对比研究； SYNTAX:左主干和(或)多支血管病的DES和CABG对比研究； COMBAT:左主干和(或)多支血管病的DES和CABG的对比研究。,63,目前认识 Understanding at present,DES总体是有较好效果的，但长期应用安全性仍有待大规模临床试验加以验证； DES术后更应强调坚持规范二联抗血小板治疗，至少1年以上，以减少支架血栓的发生； 大约6075%接受DES治疗的患者实际上并不一定需要DES，临床应严格掌握适应症；,64,Stent vs CABG,在左主干和/或多支病变中，CABG有优势; 在美国，只有18%的左主干和/或三支病变患者选择支架植入; 在欧洲，在复杂病变血运重建中，CABG仍占有主导优势。,65,关注冠心病Hybrid技术 Pay attention to Hybrid treatment,冠心病杂交手术(Hybrid技术)： 联合应用介入治疗/搭桥手术, 优势互补,一站式完成 再血管化,是冠心病治 疗的重要发展方向。,66,Life Wide Open 开放生命,67,危险因素 单一控制,危险因素 复杂干预,冠心病治疗观念改变之六 Sixth Change in Concept of CHD Treatment,68,Diabetes,Dyslipidemia,Hypertension,Obesity,69,多重危险因素的干预 Interventions for multi-RF,单一危险因素的治疗常可使病人心脑血管病危险下降20%30%，意味着还有70%80%的剩余危险需要降低,70,Polypill:心脏病一/二级予防 Polypill Approach for Class I & II Prevention of Cardiac Diseases,组成:辛伐他汀40mg, ACEI(赖诺普利), 半量噻嗪类利尿剂(或阿替洛尔25mg),低剂量阿司匹林,叶酸; Composition: Simvastatin 40mg, Lisinopril, half-dose Atenolol, low dose aspirin, folic acid (BMJ 2003; 326:1407, 1419,