他汀在抗动脉粥样硬化中的地位PPT医学课件.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,以循证医学指导临床实践,他汀在动脉粥样硬化防治中的作用,Roberts WC.Am J Cardiol,1996,78:377-378.,这是一类,神奇的药物,，,他汀对动脉粥样硬化的疗效，,如同青霉素治疗感染性疾病，,对冠心病病人，要,充分使用他汀,！,美国心脏病学杂志主编,Roberts WC,动脉粥样硬化,伴随一生的风险,泡沫细胞,脂纹,中期损伤,粥样硬化,纤维斑块,复合性病变,/,破裂,内皮功能失调,10,岁开始,30,岁开始,40,岁开始,脂质沉积为主,平滑肌细胞和胶原,血栓出血,Pepine CJ.Am J Cardiol.1998;82(suppl 10A):23S-27S.,Yu-lu Zhao et al J Hong Kong College of Cardiol 2000,8:77,Collaboration group.Chinese J Pathology 1983,12(2):81,尸检研究提示：动脉粥样硬化贯穿一生,(Age),(%),58,74,87,90,95,100,10,21,37,43,50,40,0,20,40,60,80,100,40-,50-,60-,70-,80-,90-,动脉粥样硬化,狭窄,中国人冠脉粥样硬化发生率（,1983,年）,(%),0,15,30,45,34%,27%,主动脉,冠状动脉,15-39,岁中国人冠脉和主动脉,III,型动脉粥样硬化发生率（,2000,年）,动脉粥样硬化累及全身血管床,冠状动脉疾病,脑血管疾病,外周动脉疾病,3.8%,11.9%,3.3%,24.7%,19.2%,7.4%,29.9%,3.8%,11.8%,3.3%,CAPRIE Steering Committee.Lancet 1996;348:1329-1339,有缺血性事件史的患者：事件再发风险更高,比普通人群的风险升高,心肌梗死,卒中,23,倍,(,包括心绞痛和猝死*,),1,9,倍,2,57,倍,(,包括死亡,),3,34,倍,(,包括,TIA),1,4,倍,(,仅包括致死性,MI,和其它,CHD,死亡,),4,23,倍,(,包括,TIA),2,*,猝死的定义是记录到的,1,小时内的死亡，死因是冠心病,(CHD);,仅包括致死性,MI,及其它,CHD,死亡,;,不包括非致死性,MI,1.Kannel WB.J Cardiovasc Risk 1994;,1:,333339.,2.Wilterdink JI,Easton JD.Arch Neurol 1992;,49:,857863.,3.Adult Treatment Panel II.Circulation 1994;,89:,13331363.,4.Criqui MH et al.N Engl J Med 1992;,326:,381386.,缺血性卒中,心肌梗死,周围动脉疾病,他汀在抗动脉粥样硬化中的地位，逐渐得到肯定,12,年坚持探索的循证历程,针对特定的高危患者群，使他汀应用范围更广泛,ACS,，老年人，糖尿病，高血压,不仅仅与安慰剂对照,与常规治疗或活性药物对照,早期研究与安慰剂相比，证实他汀可降低死亡率和心血管事件发生率,1994,4S,1995,WOSCOPS,1996,CARE,1998,AFCAPS/TexCAPSLIPID,2001,MIRACL,2002,HPS,PROSPERALLHAT LLT,2003,ASCOT-LLA,2004,PROVE ITALLIANCECARDSA to Z,2005,TNTIDEAL,在已接受现代治疗的稳定型冠心病患者，证实了更积极的他汀治疗能进一步获益,2006,SPARCL,证实了他汀在卒中二级预防的作用,他汀，各种指南均强烈推荐的抗动脉粥样硬化药物,NCEP ATPIII,（,2001,2004,）,Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines,ADA,Standards of Medical Care in Diabetes2006,AHA/ACC,（,2006,）,AHA/ACC Guidelines for Secondary Prevention for Patients With Coronary and Other Atherosclerotic Vascular Disease,：,2006 Update,AHA/ASA,（,2006,）,Primary Prevention of Ischemic Stroke,Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack,中国成人血脂异常防治指南（,2006,）,他汀，显著降低各种心血管事件,他汀用于一级预防，显著降低事件,研究,他汀剂量,(vs,安慰剂,),平均随访,时间,主要终点事件,降低,(%),WOSCOPS(1995),普伐他汀,40 mg,4.9,年,31,AFCAPS/TexCAPS(1998),洛伐他汀,20-40 mg,5.2,年,37,PROSPER*(2002),普伐他汀,40 mg,3.2,年,15(NS),HPS*(2002),辛伐他汀,40 mg,5.0,年,27,ASCOT-LLA,(2003),阿托伐他汀,10 mg,3.3,年,36,CARDS,(2004),阿托伐他汀,10 mg,3.9,年,37,Shepherd J et al.N Engl J Med.1995;333:1301-1307;Downs JR et al.JAMA.1998;279:1615-1622;Shepherd J et al.,Lancet.2002;360:1623-1630;Heart Protection Study Collaborative Group.Lancet.2002;360:7-22;Sever PS et al.Lancet.2003;361:1149-1158;Colhoun HM et al.Lancet.2004;364:685-696.,*Subgroup with no prior coronary heart disease(CHD).,Terminated early because prespecified early stopping rule for efficacy had been met.RRR=relative risk reduction;1 EP=primary end point;NS=not significant.Primary end points:WOSCOPS=combination of nonfatal MI,or death from CHD as a first event;AFCAPS/TexCAPS=first acute major event defined as fatal or nonfatal MI,unstable angina,or sudden cardiac death;PROSPER=composite of coronary death,nonfatal MI,and fatal or nonfatal stroke;HPS=mortality and fatal or nonfatal vascular events;ALLHAT=all-cause mortality;ASCOT=nonfatal MI and fatal CHD;CARDS=time to first occurrence of acute coronary heart disease events,coronary revascularization,or stroke.,他汀用于二级预防，显著降低事件,研究,他汀剂量,(vs,安慰剂,*,),平均随访,时间,主要终点事件,降低,(%),4S(1994),辛伐他汀,20-40 mg,5.4,年,30,CARE(1998),普伐他汀,40 mg,5.0,年,32,LIPID(1998),普伐他汀,40 mg,6.1,年,24,HPS,(2002),辛伐他汀,40 mg,5.0,年,24,GREACE(2002),阿托伐他汀,10-80 mg vs,常规治疗,3.0,年,51,ALLIANCE(2004),阿托伐他汀,10-80 mg vs,常规治疗,51.5,月,17,TNT(2005),阿托伐他汀,80mg vs 10mg,4.9,年,22,IDEAL(2005),阿托伐他汀,80mg vs,辛伐他汀,20-40mg,4.8,年,11,Scandinavian Simvastatin Survival Study Group.Lancet.1994;344:1383-1389;Lewis SJ et al.Ann Intern Med.,1998;129:681689;LIPID Study Group.N Engl J Med.1998;339:1349-1357;HPS Collaborative Group.Lancet.,2002;360:7-22;Athyros VG et al.Curr Med Res Opin.2002;18:220-228;Koren MJ et al.J Am Coll Cardiol.2004;,44:1772-1779.,*In all trials apart from GREACE and ALLIANCE.Subgroup with prior CHD.Primary end points:4S=total mortality;CARE=5-year event rates of major coronary events(coronary death,nonfatal MI,angioplasty,or bypass surgery)and stroke;LIPID=CHD mortality;HPS=mortality and fatal and nonfatal vascular events;GREACE=death,nonfatal MI,unstable angina,congestive heart failure,revascularization,and stroke;ALLIANCE=time to first cardiac event.,他汀显著降低,ACS,患者的事件,研究,他汀剂量,平均随访,时间,主要终点事件降低,(%),MIRACL*(2001),阿托伐他汀,80 mg vs,安慰剂,16,周,16,PROVE IT(2004),普伐他汀,40 mg,vs,阿托伐他汀,80 mg,2,年,16,A to Z (2004),安慰剂,+,辛伐他汀,20 mgvs,辛伐他汀,40 mg and 80 mg,721,日,11(NS),Schwartz GG et al.JAMA.2001;285:1711-1718;Cannon CP et al.N Engl J Med2004;350:1495-1504;de Lemos JA et al.JAMA.2004;292:1307-1316.,*Statin dose vs placebo.,Primary end points:MIRACL=death,nonfatal acute MI,cardiac arrest with resuscitation,or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization;PROVE IT=time from randomization to first occurrence of:death from any cause,MI,documented unstable angina requiring rehospitalization,revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting,and stroke;A to Z=composite of CV death,nonfatal MI,readmission for ACS,and stroke.,他汀中，阿托伐他汀（立普妥）唯一积累多项证据显示：使不同危险人群获益,Moderate,High,Highest,ASCOT-LLA,CARDS,TNT,REVERSAL,MIRACLPROVE IT,SPARCL,IDEAL,美国,FDA,基于,TNT,和,IDEAL,研究结果新近批准了立普妥,针对心脏病患者的,5,种新适应征,:,非致死性心肌梗死；,致死性或非致死性脑卒中；,某些类型心脏手术；,因心力衰竭住院；,(,立普妥是第一个被,FDA,批准可用于此病的降胆固醇药物）,心绞痛,阿托伐他汀（立普妥）显著降低各类人群的心血管事件在各种人群的临床终点研究一致证实：,16,周,80mg,80mg,MIRACL,ACS,(n=3.086),ACS,研究,二级预防研究,一级预防研究,4.8,年,辛伐他汀,2040mg,80mg,IDEAL,冠心病,(n=8,888),2,年,4.9,年,3,年,3.9,年,（提前,2,年结束）,3.3,年,（提前,2,年结束）,普伐他汀,40mg,立普妥,10mg,常规治疗,安慰剂,安慰剂,80mg,80mg,平均,24mg,10mg,10mg,PROVE IT,ACS,(n=4,162),TNT,冠心病,(n=10,001),GREACE,冠心病,(n=1,600),CARDS,糖尿病,(n=2,838),ASCOT,高血压,(n=10,305),阿托伐他汀,剂量,对照组,研究时间,P0.0001,22,P0.001,11,P=0.07,16,P=0.048,事件,事件,事件,事件,事件,事件,卒中,SPARCL,卒中,(n=4,731),36,P=0.0005,37,P=0.001,51,16,P=0.005,事件,16,P=0.05,事件,80mg,安慰剂,4.9,年,Sever PS,et al.Lancet.2003;361:11491158.Colhoun HM,et al.Lancet.2004;364:685696.Athyros VG,et al.Curr Med Res Opin.2002;18(4):220-228.LaRosa JC,et al.N Engl J Med.2005;352:1425-1435.Pedersen TR,et al.JAMA.2005;294:2437-2445.Schwartz GG,et al.JAMA.2001;285:1711-1718.Cannon CP,et al.N Engl J Med.2004;350:1459-1504.Amarenco P,et al.N Engl J Med.2006;355:549-559,阿托伐他汀（立普妥）积累的多项循证医学证据深刻影响了各指南的修订,2004,年，,NCEP ATPIII(2001),NCEP ATP3.5(2004),ASCOT,的影响：,10,年冠心病风险,10-20,可选,LDL-C100mg/dL(,原目标,130mg/dl),PROVE IT,：,ACS,等极高危患者可选,LDL-C70mg/dL(,原目标,100mg/dl),2006,年，,AHA/ACC,冠心病二级预防的更新版指南,TNT,，,IDEAL,：冠心病患者,LDL-C,目标,100mg/dl(2.6mmol/L),，进一步降低至,70mg/dl(1.8mmol/L),是合理的,阿托伐他汀（立普妥），,用最多的研究影响了指南修订,他汀,已完成,CV,终点研究,影响指南更新的研究数目，包括,NCEP(2004),、,AHA/ACC(2006),、,ADA(2007),和,NKF(2005),阿托伐他汀,辛伐他汀,瑞舒伐他汀,依折麦布,/,辛伐他汀,10,5,4,1,0,0,0,0,CV,终点研究数据影响了最近的调脂治疗指南,1.Grundy SM et al.Circulation 2004;110:227-239;2.Smith SC et al.J Am Coll Cardiol 2006;47:2130-2139;3.American Diabetes Association.Diabetes Care 2007;30(suppl 1):S4-S41;4.National kidney FoundationCURVES,NASDAC,Pediatrics Study,降脂疗效,临床终点,替代终点,非心血管,亚组分析,ALLIANCE,ASCOT-LLA,ASPEN,AVERT,CARDS,4D,IDEAL,MIRACL,SPARCL,TNT,GREACE*,PROVE IT*,ASAP,BELLS,REVERSAL,SAGE,TREADMILL,Vascular Basis,ARBITER*,ADCLT,BONES,LEADe,糖尿病亚组,ASCOT-LLA,TNT,PROVE IT*,代谢综合征亚组,MIRACL,TNT,老年患者亚组,CARDS,PROVE IT*,阿托伐他汀里程碑研究是全球最大规模的他汀类药物临床研究：,超过,400,项临床研究项目,入选患者超过,80,000,名,阿托伐他汀,(,立普妥）循证证据：贯穿动脉粥样硬化全程,他汀，直接延缓或逆转动脉粥样硬化斑块进展,REVERSAL,：斑块容积变化,2.7,*,普伐他汀,斑块进展,-0.4,阿托伐他汀,斑块容积变化,(%),-1,0,1,2,3,P,=0.02,*Progression vs baseline(,P,=0.001);,No change vs baseline(,P,=0.98),Nissen SE et al for the REVERSAL Investigators.,JAMA,.2004;291:1071-1080.,斑块逆转,阿托伐他汀（立普妥）在多项阳性药物对照研究显示能稳定逆转斑块,研究,研究人群,干预措施,检测,手段,斑块改变,P,值,阿托伐,他汀,对照,ESTABLISH,1,ACS,20mg/d,安慰剂,IVUS,-13.1,12.8%vs.,-8.714.9%,0.0001,REVERSAL,2,CHD,80mg/d,普伐他汀,40mg/d,IVUS,-0.4%vs.,2.7%,0.02,ASAP,3,家族性高胆固醇血症,80mg/d,辛伐他汀,40mg/d,IMT,-0.031 mm vs.,0.036 mm,0.0001,ARBITER,4,高胆固醇血症,80mg/d,普伐他汀,40mg/d,IMT,-0.034 mm vs,0.025 mm,0.03,2007ACC,日本研究,5,10-20mg/d,IVUS,显示斑块消退,*,阿托伐他汀是唯一进行了“头对头”影像学研究的他汀类药物,1.Shinya Okazaki,et al.Circulation.2004;110:1061-1068.2.Nissen SE,et al.JAMA.2004;291:1071-1080.3.Smilde TJ,et al.Lancet 2001;357:57781;4.Taylor AJ,et al.Circulation.2002;106:2055-2060;5.2007ACC,会议摘要,从,降胆固醇药物,到,抗动脉粥样硬化药物,他汀类药物机制探源,循证医学的发展使对他汀的认识不断深入,:,降,LDL-C,：他汀抗动脉粥样硬化的重要机制,一级预防,0,LDL-C(mg/dL),CHD events(%),y=.0599x,3.3952,R,2,=.9305,P,=.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,安慰剂,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.,LDL-C(mg/dL),50,70,90,110,130,150,170,190,210,CHD events(%),5,10,15,20,25,30,y=0.1629x,4.6776,R,2,=0.9029,P,70 mg/dL,CRP,2 mg/L,LDL-C,2 mg/L,随访时间,(,年,),LDL-C 70 mg/dL,CRP 2 mg/L,LDL-C,70 mg/dL,CRP 2 mg/L,0.0,0.5,1.0,1.5,2.0,2.5,0.0,0.5,1.0,1.5,2.0,2.5,0.0,0.5,1.0,1.5,2.0,2.5,0.00,0.04,0.02,0.06,0.08,0.10,LDL-C 70 mg/dL,CRP 1 mg/L,Adapted from Ridker PM et al.N Engl J Med.2005;352:20-28;Ridker PM et al.Presented at AHA Scientific Sessions;2004.,除降低,LDL-C,外，他汀通过多种机制抗动脉粥样硬化,降脂,+,改善内皮功能,抗炎,抗氧化,稳定,/,逆转斑块,Wassmann S,Nickenig G.Endothelium.2003;10:23-33.,Peter Libby et al.Am J Cardiol.2006;98suppl:26P-33P,Indeed,a growing number of studies suggest that the clinical benefits of statins may exceed their effects on circulating lipid levels and may extend to direct alterations of the composition and biology of the plaque,大量研究证实，他汀的临床获益已超越了单纯降脂本身，它还能直接作用于斑块，改变其成分和生物学特性,Peter Libby,2007ACC,最新进展剖析,阿托伐他汀的循证之路，再添新篇：,其它研究的思考：,METEOR,研究的专家述评,Torcetrapib,试验：如何客观看待升高,HDL-C,？,阿托伐他汀,(,立普妥）的循证证据，进一步增加新篇,AHA/ACC 2007,年会,主要心血管事件：包括冠心病死亡、心肌梗死、卒中、某些类型的心脏手术，胸痛,冠脉事件：包括心源性死亡、心肌梗死和心脏骤停复苏,冠脉事件,2,主要心血管事件,1,卒中,终点事件,阿托伐他汀,80mg vs.,安慰剂,阿托伐他汀,10mg vs.,安慰剂,治疗药物,无心脏病史,研究期间卒中或,TIA,复发,2,型糖尿病代谢综合征,研究人群,SPARCL,再发卒中,/TIA,亚组,（,n=850,）,CARDS,代谢综合征亚组,（,n=2200,）,61%,41%,53%,AHA/ACC 2007,年会,“,给人们留下深刻印象的是阿托伐他汀心血管危险降低的幅度，使那些心血管事件高危患者群的卒中风险显著降低了,61,。”,CARDS,主要研究者、伦敦大学附属医院内分泌与代谢病学,John Betteridge,教授,“,这是,首次,显示他汀类药物可以使近期伴有卒中或,TIA,的患者冠脉获益。令人印象深刻的是阿托伐他汀在这些高危患者群中的获益程度。”,丹麦哥本哈根大学血管外科主任,Henrik Sillesen,教授,CARDS,亚组分析评论：,SPARCL,亚组分析评论：,ARMYDA-ACS,结果公布：,ARMYDA,的系列研究,阿托伐他汀在介入治疗中的作用再次被证实,患者人群,干预措施,主要终点,结果,P,值,ARMYDA-1,1,稳定型心绞痛,（,n=153,）,PCI,术前,7,天开始阿托伐,40mg/d vs.,安慰剂,心肌梗死,（定义为,CK-MB,超过正常上限,2,倍）,5%,vs.,18%,0.025,ARMYDA-3,2,择期体外循环下心脏手术,（,n=200,）,术前,7,天开始阿托伐,40mg/d vs.,安慰剂,术后发生房颤,61%,（,RR,）,0.017,ARMYDA-ACS,3,ACS,（,n=171,）,PCI,术前,12-24,小时阿托伐,80/40mg/d vs.,安慰剂，术后均阿托伐,40mg/d,术后,1,个月主要心血管不良事件,88%,（,RR,）,0.004,Pasceri V,et al.Circulation.2004;110:674-678.,Patti G,et al.Circulation.2006;114:1455-1461.,Patti G,et al.J Am Coll Cardiol 2007;49:12728.,新近研究显示，,ACS,患者中有近一半伴轻、中度肾功能不全，,阿托伐他汀在这部分患者中无需调整剂量。,0.03,0.02,0.01,0,-0.01,-0.02,-0.03,-0.04,0,6,12,18,24,0.04,METEOR,：瑞舒伐他汀,40mg,可以延缓,CIMT,进展，但是未能逆转,瑞舒伐他汀,40mg vs.,安慰剂,监测指标：,CIMT,，随访,2,年,John R.Crouse III,et al.JAMA.2007;297:1344-1353,安慰剂,瑞舒伐他汀,随访时间（月）,最大,CIMT,变化（,mm,）,METEOR,评论：瑞舒伐他汀对终点事件的影响尚需大规模临床终点研究来评价；,METEOR,研究随访,2,年，出现,6,例缺血性事件，全部发生在瑞舒伐他汀治疗组，值得思索；,METEOR,中显示，长时间使用瑞舒伐他汀，,HDL,比安慰剂组只升高,8,；,Dr.Lauer,：,METEOR,研究述评,替代终点需要结合临床硬终点研究，一起指导临床；,替代终点和临床硬终点研究的证据，需大量积累；,HDL,的量？还是质？,Lauer MS.JAMA.2007;297:1376-1378,升高,HDL-C,的,Torcetrapib,，并未带来预期的受益,研究人群,干预措施,检测指标,HDL-C,（,vs.,对照组）,是否显著逆转斑块,ILLUSTRATE,1,冠心病,Torcetrapib 60mg/d,阿托伐,vs.,阿托伐,IVUS,61%,X,RADIANCE 1,2,遗传性家族性高胆固醇血症,Torcetrapib 60mg/d,阿托伐,vs.,阿托伐,CIMT,51.9%,X,RADIANCE 2,3,混合性高脂血症,Torcetrapib,阿托伐,vs.,阿托伐,CIMT,X,Torcetrapib,相关研究（均随访,2,年）,1.Nissen SE,et al.N Engl J Med 2007;356:1304-16.,2.Kastelein JJP,et al.N Engl J Med 2007;356,3.AHA/ACC 2007,年会,尽管强化治疗使,HDL,水平升高，但却没有降低动脉粥样硬化事件的发生率；,新的治疗手段将以改善,HDL,功能为核心；,启 示,HDL-C,：质比量更重要,Torcetrapib,研究者,Daniel Rader,：,HDL-C,和心血管病危险因素间究竟只是存在关联，还是一种因果关系？尚需进一步研究。,HDL,在鳟鱼和海龟中存在，说明其进化并非是为了对动脉粥样硬化起保护作用。,在评价以,HDL,为目标的治疗手段的心血管获益时，以,HDL-C水平升高为指标既不恰当，也不必要。,发展以,HDL,为目标的治疗方法时，应更多关注,HDL,的功能，而不再是单纯的数量。,HDL,的故事，目前还充满未知,对动脉粥样硬化的干预策略,Libby P.Circulation.2001;104:365-372;Ross R.N Engl J Med.1999;340:115-126.,降低,LDL-C,是目前被证明最有效的手段之一，他汀,应该被充分应用,早期干预,严格控制,长期治疗,以升高,HDL-C,的药物为代表的新调脂药物开发任重,而道远,一般说来,HDL,越高,临床事件越少,但迄今尚无很好,检测,HDL,质量和功能检测方法,HDL,的“质”比“量”更重要,分子机制,研究,充分的,临床实践,经验,临床“硬”,终点研究,循证医学基础,临床实践,在临床中,深刻认识他汀的获益,选择循证证据,最全面、最完整、最充分,的他汀；,阿托伐他汀的证据，贯穿动脉粥样硬化（,LDL-,斑块,事件）链全程。,Topol EJ.N Engl J Med,2004:April 8,；,350,：,1562-1564,在,动脉粥样硬化血管疾病,的处理方面，,他汀,类药减少主要血管事件，,如死亡、心肌梗死和中风的疗效,已超越所有其他类的药物,。,谢谢！,以循证医学指导临床实践在动脉粥样硬化防治中充分,使用他汀,