优化高血压治疗药物的选择.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系本人改正。,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系本人改正。,The,HY,pertension in the,V,ery,E,lderly,T,rial,N.Beckett,R.Peters,A.Fletcher,C.Bulpitt,on behalf of the HYVET committees and investigators,ClinicalTrials.gov:NCT00122811,研究背景,:,老年高血压患者,(,80,岁,),人群流行病学调查显示血压水平与生存率有正相关性,临床研究很少使用老老年患者,.,荟萃分析,(n=1670),(Gueyffier et al.1997),降低,36%,卒中发生率,(BENEFIT),增加,14%(p=0.05),总死亡率,(RISK),老老年患者高血压研究,(HYVET),先期试点研究结果,(n=1273),与荟萃分析相仿,(Bulpitt et al.2003),研究特点,:,多国参与,多中心,随机双盲安慰剂对照,入选标准,:,排除标准,:,80,岁,站立,SBP 140mmHg,SBP;160-199mmHg,过去,6,月内有卒中发生,+,D,BP;11.1mmo/l),6.9%,6.8%,Total cholesterol(mmol/l),5.3,5.3,HDL Cholesterol(mmol/l),1.35,1.35,Serum Creatinine(mol/l),89.2,88.6,Uric acid(mol/l),279,280,Body Mass Index(kg/m,2,),24.7,24.7,基线数据,(,心血管危险因素,),血压变化,Median follow-up 1.8 years,15 mmHg,6 mmHg,各种卒中事件,(,降低,30%),P=0.055,全因死亡,(,降低,21%),P=0.019,致死性卒中,(,降低,39%),P=0.046,心衰,(,降低,64%),P0.0001,HR,95%CI,0.70,(0.49,1.01),0.61,(0.38,0.99),0.79,(0.65,0.95),0.81,(0.62,1.06),0.77,(0.60,1.01),0.71,(0.42,1.19),0.36,(0.22,0.58),0.66,(0.53,0.82),各种卒中,卒中死亡,全因死亡,非心因,/,未知原因死亡,心血管死亡,心性死亡,心衰,心血管事件,ITT,小结,Per-Protocol,分析,HR,95%CI,P,各种卒中,-34%,0.46-0.95,0.025,全因死亡,-28%,0.59-0.88,0.001,卒中死亡,-45%,0.33-0.93,0.021,心血管死亡,-27%,0.55-0.97,0.029,心衰,72%,0.17-0.48,0.001,心血管事件,-37%,0.51-0.71,0.001,生化指标自基线改变,(2,年群体分析,),血清以下指标无改变,:,Potassium,Uric acid,Glucose,Creatinine,在第,2,年时 治疗组有,73.4%,使用联合治疗方案,安慰剂组有,85.2%,安全事件,严重不良反应事件,(,随机分组后,),安慰剂组,448,例,治疗组,358,例,(p=0.001),5,例 可能为相关的,SADRs(,安慰剂组,3,例,治疗组,2,例,),结论,抗高血压治疗,indapamide(SR)1.5mg(,perindopril),在老老年人群中能够减少卒中死亡及全因死亡,.,卒中,NNT(2,年,)=94,;,死亡,NNT(2,年,)=40,在减少心衰事件及复合心血管事件方面也有显著和较大的收益,收益较早即有体现,该治疗方案安全性很好,注意事项,本项研究涉及人群为该类人群中较为健康的群体,对于收缩压在,160mmHg,以下人群的治疗收益尚需进一步研究,研究中血压控制目标为,150/80 mmHg,对于更低目标的收益还需进一步研究,HYVET,研究的临床提示意义,再次证明了“降压是硬道理”,那么如何优化药物选择？,年龄本身不是拒绝降压治疗的主要理由,强调首选药物的降压观念已经过时，因为大多数患者都需要,2,种或更多的药物使血压达标,需要联合用药方案,2007ESC/ESH,高血压指南,Am J Kidney Dis 2004;43(5 Suppl 1):S1-290.,Journal of Hypertension 2007,25:11051187.,噻嗪类利尿剂,ARB,ACEI,-,阻滞剂,-,阻滞剂,钙拮抗剂,Journal of Hypertension 2007,25:11051187.,实线代表普通高血压人群首选的联合用药,;,方框表示经对照干预试验证明此类药物有益,2007ESC/ESH,高血压指南,ONTARGET:The,ON,going,T,elmisartan,A,lone and in combination with,R,amipril,G,lobal,E,ndpoint,T,rial,希望回答问题,:,是否替米沙坦（,ARB,）“不劣于”雷米普利（,ACEI,）,?,是否,ACEI+ARB,由于,ACEI,?,终点事件,:,首要终点,:CV death,MI,stroke,CHF hosp,次要终点,:,CV death,MI,stroke(HOPE trial outcome),设计,:,入组,n=29,019,随机，双盲，双模拟,733,个中心,40,个国家参加,n=25,620,随访,56,个月,治疗药物 用法,洗脱期,(,单盲,),Day 1-3Ram 2.5 mg+Tel Placebo,Day 4-10Ram 2.5 mg+Tel 40 mg,Day 11-18Ram 5.0 mg+Tel 40 mg,随机化,(,双盲,),2 weeksRam Placebo+Tel 80 mg,Ram 5 mg+Tel Placebo,Ram 5 mg+Tel 80 mg,ThenFull doses(Tel 80 mg daily,Ram 10 mg daily)for the 3 arms,没有随机化处理的原因,%,完成洗脱,(n=29,018),100,没有随机化,11.71,肌酐增加,0.22,钾升高,0.77,持续的症状性低血压,1.70,死亡,0.09,全部医学原因,2.78,依从性,75%,3.87,其他原因,3.01,患者决定,2.06,全部患者原因,5.93,主要的基线特点,雷米普利,替米沙坦,联合,N,8576,8542,8502,年龄,66.4,66.4,66.5,%,女性,27.2,26.3,26.5,%CAD,74.4,74.5,74.7,%Stroke/TIA,21.0,20.6,20.9,%,糖尿病,36.7,38.0,37.9,BP,141.8/82.1,141.7/82.1,141.9/82.1,他汀,61.0,62.0,61.8,抗血小板,80.5,81.1,81.1,-blocker,56.5,56.9,57.4,血压的变化,(mmHg),雷米普利,替米沙坦,联合,收缩压,-6.0,-6.9,-8.4,舒张压,-4.6,-5.2,-6.0,终止使用研究药物的比较,ONTARGET,Years of Follow-up,Cumulative Hazard Rates,0.0,0.1,0.2,0.3,0.4,0,1,2,3,4,Telmisartan,Ramipril,#at Risk,Yr 1,Yr 2,Yr 3,Yr 4,T,8542,7954,7384,6909,6478,R,8576,7796,7165,6681,6254,终止使用研究药物的原因,Ram,N=8576,Tel,N=8542,Tel vs.Ram,RR P,低血压,149,229,1.54,0.0001,晕厥,15,19,1.27,0.4850,咳嗽,360,93,0.26,0.0001,腹泻,12,19,1.59,0.20,血管性水肿,25,10,0.40,0.0115,肾功能损伤,60,68,1.14,0.46,任何终止,2099,1962,0.94,0.02,首要终点事件比较,ONTARGET,Primary Outcome&HOPE Primary Outcome,Ram,Tel,Tel vs Ram,N(%),N(%),RR(95%CI),P(non-inf),N,8576,8542,Primary Outcome,CV Death,MI,Stroke,CHF Hosp,1412(16.46%),1423(16.66%),1.01(0.94-1.09),0.0038,(Adjusted for SBP),1.02(0.95-1.10),0.0055,HOPE Primary Outcome,CV Death,MI,Stroke,1210(14.11%),1190(13.93%),0.99(0.91-1.07),0.0009,(Adjusted for SBP),0.99(0.91-1.07),0.0012,ONTARGET,非劣势比较,ONTARGET,ACEI+ARB vs ACEI,首要终点事件比较,ONTARGET,终止使用研究药物的原因,Ram,N=8576,Ram+Tel,N=8502,Ram+Tel vs.Ram,RR P,低血压,149,406,2.75,0.0001,晕厥,15,29,1.95,0.032,咳嗽,360,392,1.10,0.1885,腹泻,12,39,3.28,0.0001,血管性水肿,25,18,0.73,0.30,肾功能损伤,60,94,1.58,0.0050,任何原因终止,2099,2495,1.20,0.0001,结论,:,替米沙坦,VS,雷米普利,无论是首要还是次要终点事件，替米沙坦不劣于雷米普利,在副作用方面，替米沙坦略优于雷米普利,更少的咳嗽和血管性水肿,虽然有更多轻微的低血压发生，但是并没有比雷米普利有更多的严重性低血压发生，比如晕厥,结论：替米沙坦,+,雷米普利,VS,雷米普利,ACEI+ARB,的组合不仅在终点事件方面没有由于单用,ACEI,，而且还会有更多的副作用发生,ONTARGET,研究的临床提示意义,ACEI+ARB,双阻断,RAAS,不是一个可以广泛采用的降压联合治疗方案,ONTARGET,那么如何优化降压药物联合治疗方案的选择？,2005,2008,+,第一个严格意义上的降压联合方案的大规模研究,:,欧洲最大的高血压研究,ASCOT,ASCOT,研究设计,氨氯地平,培哚普利,阿替洛尔,苄氟噻嗪,19,257 名,高血压患者,PROBE,设计,ASCOT-BPLA,主要终点：非致死性心肌梗死及致死性冠心病,安慰剂,阿托伐他汀 10,mg,双盲,ASCOT-LLA,10,305 患者,TC 6.5 mmol/L(250 mg/dL),ASCOT：,络活喜组降压优于阿替洛尔组,mm Hg,60,80,100,120,140,160,180,Time(years),Baseline,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,阿替洛尔,苄氟噻嗪,氨氯地平,培哚普利,137.7,136.1,79.2,77.4,Mean difference 1.9,Last visit,Mean difference 2.7,SBP,DBP,163.9,164.1,94.8,94.5,ASCOT:,终点事件发生率,(,苯磺酸氨氯地平,+/-,培哚普利,vs,阿替洛尔,+/-,苄氟噻嗪,),*,P0.05,降低百分比,(%),-35,-30,-25,-20,-15,-10,-5,0,*,*,*,*,*,*,*,非致死心梗,和冠心病死亡,心血管,死亡,总死亡,总冠脉事件,致死,/,非致死性,卒中,总心血管,事件和,介入,新发,糖尿病,肾损害,Dahlof B,Sever P,et al.Lancet.2005;366:895-906.,*,A,voiding,C,ardiovascular Events through,COM,bination Therapy in,P,atients,LI,ving with,S,ystolic,H,ypertension,Kenneth Jamerson,1,George L.Bakris,2,Bjorn Dahlof,3,Bertram Pitt,1,Eric J.Velazquez,4,and Michael A.Weber,5,for the ACCOMPLISH Investigators,University of Michigan Health System,Ann Arbor,MI,1,;University of Chicago-Pritzker School of Medicine,Chicago,IL,2,;Sahlgrenska University Hospital,Gothenburg,Sweden,3,;Duke University School of Medicine,Durham,NC,4,;SUNY Downstate Medical College,Brooklyn,NY,5,Clear data,Clear win,and a Clear message,Accomplish,challenges,current,guidelines,!,ACC,对,Accomplish,研究的新闻评论,ACCOMPLISH:,一项独特的高血压研究,传统的高血压研究,:,以单药治疗起始,逐渐加药以致血压达标,ACCOMPLISH:,以单片复方药物治疗起始治疗高危高血压,某些特殊复方药物组合可能有降压外器官保护作用,ACCOMPLISH:,研究设计,Jamerson KA et al.,Am J Hypertens,.2003;16(part2)193A,*Beta blockers;alpha blockers;clonidine;(loop diuretics).,14 Days,Day 1,Month 1,Month 2,Year 5,Screening,Amlodipine 5 mg+benazepril 20 mg,Randomization,Benazepril 40 mg+HCTZ 12.5 mg,Benazepril 40 mg+HCTZ 25 mg,Free add-on antihypertensive agents*,Month 3,Free add-on antihypertensive agents*,Amlodipine 5 mg+benazepril 40 mg,Amlodipine 10+benazepril 40 mg,Benazepril 20 mg+HCTZ 12.5 mg,Titrated to achieve BP140/90 mmHg;130/80 mmHg in patients with diabetes or renal insufficiency,Primary Endpoint,研究的首要终点,心血管发病率与死亡率,:,心因性死亡,非致死性心梗,非致死性卒中,因不稳定性心绞痛入院,冠脉重建术,(PCI or CABG),心脏复苏后猝死,(Resuscitated sudden death),Jamerson KA et al.,Am J Hypertens,.2003;16(part2)193A.,ACCOMPLISH,入选标准,男性,女性,55,岁,SBP 160 mmHg,或正在接受高血压治疗,心血管及肾脏损害依据,基线特征,ACEI/HCTZ,N=5741(%),CCB/ACEI,N=5721(%),性别,男性,女性,3509(61.1),2226(38.8),3436(60.1),2283(39.9),种族,白人,黑人,亚洲,其他,4789(83.4),699(12.2),27 (0.5),220(3.8),4814(84.1),675(11.8),22(0.4),208(3.6),年龄,平均,(,岁,),70,70,68.3,3407(59.3),2328(40.6),68.4,3367(58.9),2351(41.1),地区,北欧*,美国,1676(29.2),4059(70.7),1677(29.3),4042(70.7),*,Denmark,Finland,Norway or Sweden,收缩压变化,mm Hg,Month,57315387520649994804428525201045,57095377515449804831428625941075,Patients,ACEI/HCTZ,N=5733,CCB/ACEI,N=5713,*,Mean values are taken at 30 months F/U visit,129.3 mmHg,130mmHg,差值,0.7,mmHg p0.05*,DBP:71.1,DBP:72.8,基线,控制率,37.2,37.9,ACCOMPLISH:,起始为联合治疗的控制率,ACEI/HCTZ,N=5733,控制率,(%),CCB/ACEI,N=5713,10,20,30,40,50,60,70,80,90,78.5,81.7,P0.001,随访,30,月时,对照组为,140/90 mmHg,ACCOMPLISH,研究提前中止,DSMB Oct 17 2007,在研究进展到,60%,时,提前到达预先设定的有效性指标,因此研究提前中止,.,末次病人数据采集,:2008,年,1,月,24,日,首要终点的,Kaplan-Meier,曲线,累积事件发生率,HR(95%CI):0.80(0.72,0.90),20%Risk Reduction,到达首发,CV,事件的时间,(,天,),p=0,ACEI/HCTZ,CCB/ACEI,650,526,.0,0,0,2,中期 数据,Mar 08,20%,0.5,1.0,2.0,首要终点的分析,复合,CV,死亡率,/,发病率,CV,死亡率,非致死性心梗,非致死性卒中,因不稳定性心绞痛入院,冠脉重建术,心脏复苏后猝死,Incidence of adjudicated primary endpoints,based upon cut-off analysis date 3/24/2008,(Intent-to-treat population),Risk Ratio(95%),Favors,CCB/ACEI,Favors,ACEI/HCTZ,0.80(0.720.90),0.81(0.62-1.06),0.81(0.63-1.05),0.87(0.67-1.13),0.74(0.49-1.11),0.85(0.74-0.99),1.75(0.73-4.17),中期 数据,Mar 08,首要及次要终点,复合,CV,死亡率,/,发病率,首要事件伴,/,无,冠脉重建术,严重,CV,终点事件,(CV,死亡,非致死性,MI,致死性卒中,),全因死亡,Incidence of adjudicated primary endpoints,based upon cut-off analysis date 3/24/2008,(Intent-to-treat population),Risk Ratio(95%),0.80(0.720.90),0.79(0.680.92),0.80(0.680.94),0.90(0.751.08),0.5,1.0,2.0,Favors,CCB/ACEI,Favors,ACEI/HCTZ,中期数据,Mar 08,结论（,1,）,平均研究观察,30,个月后,总体血压控制率从,37%,增加到,80%,平均,SBP,从,145,下降到,130,mmHg,50%,患者只用单药复方治疗控制血压,.,经过平均,39,月的随访,CCB+ACEI,优于,ACEI+,利尿剂,CV,发病率,/,致死率下降,20%,(p=0.0002),CV,一级硬终点,(CV,死亡,卒中及心梗,),下降,20%,(p=0.007),结论（,2,）,ACCOMPLISH,研究采用的治疗方案达到了非常,卓越的血压控制率,，为成千上万高血压患者的治疗带来了新的选择,ACCOMPLISH,研究结果,挑战现有指南,中,以利尿剂为基础,的联合治疗方案,专家评论（一）,Dr.Venkata Ram,Accomplish,为起始采用联合治疗,提供了,重要的数据,Accomplish,再次,肯定了,ACEI/ARB,在高血压长期治疗中的作用,Accomplish,结果证明，,从此,无需怀疑,DHP-CCB,（,络活喜）在靶器官保护治疗策略中的份量,Accomplish,结果,挑战,现有指南提倡的,利尿剂,在初始治疗中的地位,专家评论（二）,Dr.,Michael,Weber,根据,ACCOMPLISH,研究结果，应该肯定的是,:,利尿剂在高血压治疗策略中的地位会被改变,DHP-CCB,（如络活喜）会被推荐为高血压治疗策略中必不可少的一部分,Im sure that recommendation will change.it will take away the recommendation for diuretics,and adding the calcium-channel blocker will invariably be a part of that.“,Michael Weber,专家评论（三）,Dr.,Salim,Yusuf,“Based on the presented data,the ACCOMPLISH study,will challenge,current guidelines.”,关注几个显著的事实,ASCOT,和,ACCOMPLISH,研究,均提前终止,ASCOT,和,ACCOMPLISH,研究,均全面更多获益,ACCOMPLISH,：血压控制率：,37%,VS,80%,ACCOMPLISH,：,血压和获益,0.7mmHg,VS,20%,ASCOT,和,ACCOMPLISH,均选择了络活喜,讨论,0.7 mmHg,的血压差距带来了,20%,的终点获益优势，是否和络活喜的,全面高质量降压作用,有关？,尽管,ASCOT,和,ACCOMPLISH,选用的,CCB,是络活喜，但,是否其他,CCB,也有类似作用,？,