从循证医学看CCB在高血压防治地位

,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,从循证医学看,CCB,在高血压防治中的地位,温州医学院附属第一医院 心内科,吴高俊,主任,降压治疗目标,JNC-7,指出降压治疗的最终目标,降压达标,目标值,:140/90 mmHg,合并糖尿病,肾脏疾病,:130/80mmHg,减少心脑血管,肾脏并发症和死亡率,The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,降压治疗的目的：最大限度减少心脑血管事件,降压,达标,减少,事件,根本 关键,目的 收益,降压是硬道理！微小的血压差异，显著的心血管收益,治疗组间的血压差异与卒中、,CHD,、,主要,CVD,事件、,CVD,死亡及总死亡率风险的差异直接相关,Lancet 2003;362:1527-45,0,-5,-10,-15,-20,-25,-30,卒中,CHD,心衰,总死亡,23%,15%,16%,14%,4/3 mmHg,N20 888,主要,CV,事件,15%,降压治疗,脑卒中,冠心病事件,延长病人生命,Paolo,Verdecchia,et,al.Hypertension 2005;46;386-392,CCB,与,ACEI,降压治疗对脑卒中事件的降低,随机组间收缩压的差值（,mmHg,）,CAPPP,PEACE,PROGRESS,PROGRESSCom,CAMELOT,EUROPA,HOPE,ANBP2,STOP2/ACE-I,ALLHAT/ACE-I,IDNT2,CAMELOT,Syst,-China,SYST-EUR,STONE,PREVENT,CONVINCE,MIDAS,INSIGHT,NORDIL,STOP2/CCB,ALLHAT/CCB,INVEST,NORDIL,SHELL,.2,.4,.4,.8,1,1.2,1.4,2.0,1.8,-5,0,5,10,15,-5,0,5,10,15,ELISA,卒中事件,OR,ACEI,CCB,PART-2,LIKPDS39,SCAT,NICOLE,ACTION,NICS,VHAS,Paolo,Verdecchia,et,al.Hypertension 2005;46;386-392,CCB,与,ACEI,降压治疗对冠心病事件的降低,LIKPDS39,PEACE,PROGRESS,PROGRESSCom,CAMELOT,EUROPA,HOPE,ANBP2,STOP2/ACE-I,CAPPP,ALLHAT/ACE-I,IDNT2,CAMELOT,Syst,-China,SYST-EUR,STONE,PREVENT,ACTION,NICOLE,INSIGHT,NORDIL,STOP2/CCB,ALLHAT/CCB,VHAS,CONVINCE,INVEST,.2,.4,.4,.8,1,1.2,1.4,2.0,1.8,-5,0,5,10,15,-5,0,5,10,15,ELISA,冠心病事件,OR,随机组间收缩压的差值（,mmHg,）,ACEI,CCB,SHELL,NICS,与目前,ALLHAT,研究的结果一致，,CCBs,与,ACEI,相比，在预防卒中方面能够提供独立的降压外益处（,14,，,p,0.042,）；,而同时，,ACEI,与,CCBs,相比，也能提供关于冠心病方面的额外益处（,10,，,p,0.028,）,Franz H. Messerli et al. Hypertension. 2006;48:359-361.,欧洲稳定心绞痛治疗指南可以改善预后的药物,阿司匹林,阻滞剂,他汀,ACEI,（高血压、心衰、左室功能不全、糖尿病）,长效,CCB,未列入其中,European Heart Journal (2006) 27, 13411381,欧洲,ESC,稳定型心绞痛治疗指南,快速、短期,缓解症状,长期缓解,心绞痛症状,症状不能控制,加用二氢吡啶类,CCB,不能耐受或无效,长效硝酸酯药,舌下或口服,硝酸酯类药,使用,Beta-,受体阻滞剂,证据强度,1 C,1 A,1 A,1 B,European Heart Journal (2006) 27, 13411381,追溯,2004,年,9,月：,ACTION,研究,A,C,oronary disease,T,rial,I,nvestigating,O,utcome,with,N,ifedipine,GITS,硝苯地平控释剂治疗冠心病终点研究,结果发表在,Lancet,杂志,Lancet 2004;364:84957,目的：稳定型心绞痛患者，观察现代常规治疗基础上加用长效,CCB,硝苯地平控释剂对心血管的安全性和有效性,ACTION,研究方案,在冠心病常规治疗基础之上加用,安慰剂,qd,n=3,840,在冠心病常规治疗基础之上加用,硝苯地平控释剂,3060mg,qd,n=3,825,0,1,2,3,4,5,年,研究结束,7,665,例,稳定型心绞痛患者,6,Lubsen,J, Poole-Wilson PA,Pocock,SJ, et al.,Eur,Heart J 1998;19(suppl I):I2032.,ACTION,研究结果,0.0,0.2,0.4,0.6,0.8,1.0,0,2,4,6,年,无事件生存率,%,硝苯地平,安慰剂,全因死亡 (,p=0.4),RA=,难治性心绞痛,PREV=,外周血管重建术,CVA =,致残性脑卒中,一级有效性终点(死亡、,MI, RA, HF, CVA, PREV p=0.5),一级安全性终点 (死亡,MI, CVA, p=0.9),ACTION,研究：一级安全性终点,22,0.78 (0.10),99,77,致残性卒中,4,1.04 (0.62),257,267,心梗,7,1.07 (0.41),291,310,全因死亡,变化率(%),危险度 (,p,值),安慰剂组,(,n),硝本地平控释片,(,n),终点,Philip A Poole-Wilson,et al. Lancet 2004; 364: 84957,欧洲稳定型心绞痛,2006,年指南,The authors concluded that,nifedipine,treatment is safe and reduces the need for coronary interventions.,However, the lack beneficial effects of,nifedipine,on hard endpoints may,not,satisfy the requirements for cardiovascular safety.,The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology.European Heart Journal (2006) 27, 13411381,0.20,0.15,0.10,0.05,0.00,0 1 2 3 4 5 6 7,基线,CHD,氨氯地平,赖诺普利,一级终点事件发生时间（年）,赖,/,氨,1.06(0.99-1.32) 0.69,RR(95%Cl),P,值,累计,CHD,发生率,0.20,0.15,0.10,0.05,0.00,0 1 2 3 4 5 6 7,基线无,CHD,氨氯地平,赖诺普利,赖,/,氨,0.98(0.88-1.13) 0.78,RR(95%Cl),P,值,氨氯地平与赖诺普利对,CHD,患者预防致死,/,非致死性冠心病疗效相同,ALLHAT,一级终点事件发生时间（年）,Frans H.H. Leenen et al. Hypertension. 2006;48:374-384.,CAMELOT,：,主要复合终点心血管不良事件,*,络活喜,(,苯磺酸氨氯地平,),与安慰剂相比，风险降低,31%,(,P,=0.003),络活喜与依那普利相比，风险降低,19%,(,P,=0.10),依那普利与安慰剂相比，风险降低,15%,(,P,=0.16),*心血管死亡,非致死性心肌梗死,心脏骤停行复苏术,冠状动脉血运重建术,因心绞痛住院,因充血性心力衰竭住院,致死性,/,非致死性脑卒中或短暂脑缺血发作,任何新发外周血管疾病,.,Nissen,et al, for the CAMELOT investigators.,JAMA,. 2004;292:2217-2226.,各时期存在危险性的人数,安慰剂,655588558525488,依那普利,673608572553529,络活喜,663623599574535,累积不良事件比率,月,0,6,12,18,24,0,0.25,0.20,0.15,0.10,0.5,安慰剂,依那普利,络活喜,31%,19%,15%,P=0.16,P=0.10,P=0.003,高危冠心病,病人降压治疗获益应该更大但不同药物之间存在差别,研究名称 药物收缩压降低心肌梗死,HOPE,雷米普利,-3.3mmHg,29%,EUROPA,培哚普利,-5.0mmHg,31%,ACTION,硝苯地平控释片,-6.0mmHg,4%,CAMELOT,氨氯地平,-4.8mmHg,27%,CCB,与安慰剂对照的二级预防研究：不同,CCB,对心肌梗死预防效果不同,Jan A.,Staessen,et,al.,Hypertens,Res,2005; 28: 385407,氨氯地平研究均显示降压可以减少心肌梗死,而硝苯地平及尼索地平不行,预测,比值比,实际观察,比值比,1.04,1.25,0.76,0.73,0.59,0.79,0.79,0.74,0.71,0.76,硝苯地平,尼索地平,氨氯地平,30-60,20-40,5-10,ACTION(7665),NICOLE(819),PREVENT(825),CAMELOT(1318),IDNT2(1136),6.8,3.5,4.7,2.5,6.4,0.002,0.18,0.95,0.82,0.24,137/80,129/78,129/78,129/78,159/87,6.0,9.1,6.8,4.8,5.0,DHP,Dosage(mg/d),Trial(n),%withMI,MI,Observed and predicted odds ratios(95%CI),P,BP(mmHg),SBP(mmHg),2.86,氨氯地平减少心肌梗死的获益幅度和,ACEI,相当,Jan A.,Staessen,et,al.,Hypertens,Res,2005; 28: 385407,2.86,1.04,0.76,0.25,0.71,0.76,0.74,0.73,0.79,0.59,0.79,0.79,0.79,0.79,0.79,0.66,0.93,0.61,0.80,0.55,0.79,0.93,0.79,0.79,0.65,0.70,0.69,1.00,0.89,DHP,Dosage(mg/d),Trial(n),%withMI,MIObserved and predicted odds ratios(95%CI),P,BP(mmHg),SBP(mmHg),硝苯地平,尼索地平,氨氯地平,30-60,20-40,5-10,ACTION(7665),NICOLE(819),PREVENT(825),CAMELOT(1318),IDNT2(1136),6.8,3.5,4.7,2.5,6.4,0.002,0.18,0.95,0.82,0.24,137/80,129/78,129/78,129/78,159/87,6.0,9.1,6.8,4.8,5.0,雷米普利,10,HOPE(9297),11.1,5-10,PART2(617),8.9,1.25,5-20,10-20,4,4+2.5 Ind.,4-8,5-10,DIABHYCAR(4912),SCAT(460),CAMELOT(1332),PROGRESS/Mono(2561),PROGRESS/Comb(3544),EUROPA(12218),PEACE(8290),依那普利,培哚普利,l,群多普利,l,2.8,4.6,2.3,4.4,4.4,6.0,5.1,0.35,0.52,0.35,0.60,0.34,0.43,0.65,0.29,0.27,139/79,133/79,145/82,130/78,129/77,147/86,147/86,137/82,134/78,3.3,5.0,1.5,4.0,4.9,5.0,12.0,5.0,0.2,ACEI,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.8,有利于治疗组,有利于安慰剂,预测,比值比,实际观察,比值比,31%,18%,4%,+1,%,P=0.031,P=0.009,P=0.26,P=0.89,VS.,安慰剂,VS.,ACEI,VS.,ARB,VS.,利尿剂,/,受体阻滞剂,(%),Messerli FH, et al. Hypertension. 2006;48:359-361.,PREVENT (n=825),CAMELOT (n=1318),IDNT (n=1136),ALLHAT/,Lis,(n=18102),CAMELOT/,Ena,(n=1336),IDNT/,Irb,(n=1146),VALUE (n=15245),ALLHAT/,Diu,(n=24309),ASCOT (n=19257),Hypertension,杂志,2006,年,9,月刊最新荟萃分析：,降低,冠心病事件,，络活喜优于安慰剂及,ARB,，与,ACEI,相当,ACTION,NORDIL,INSIGHT,STOP-2-A,STOP-2-C,ALLHAT-A,ALLHAT-D,INVEST,CONVINCE,ASCOT,VALUE,Syst-Eur,Syst-China,IDNT-,pbo,IDNT-Irbe,CCB,与对照药物收缩压差值,(mm Hg),-5 0 5,10 15,0.50,0.75,1.00,1.25,1.50,氨氯地平的临床研究均符合降低血压减少冠心病事件的规律,冠心病的相对风险比,William J. Elliott,et al. Circulation 2006;113:2763-2772,无独有偶欧洲学者,05,进行的荟萃分析同样提示,Paolo,Verdecchia,et,al.Hypertension,2005;46;386-392,Paolo,Verdecchia,et,al.Hypertension,2005;46;386-392,为何氨氯地平减少心肌梗死效果优于其他,CCB,？,为什么络活喜的循证研究百战不殆,？,透过现象看本质,络活喜,的独特降压优势,A,24小时持久降压,充分控制清晨高血压,降低心脑血管事件危险,B,平稳降压,不引起反射性交感神经,兴奋性增强,安全用于心衰患者,清晨高血压,:,触发心脑血管事件的重要因素,Thomas Giles, J,Hypertens,2005,23 (,suppl,1):S35S39,清晨血压升高,血压升高,剪切力,斑块破裂,动脉血栓形成,心脑血管事件,心率增快,儿茶酚胺峰值升高清晨高凝状态,络活喜,24,小时持久降压,有效控制清晨血压,络活喜,显著降低清晨血压升高速度,优于其他钙离子拮抗剂,C. Macchiarulo et al. Cur Ther Res Clin Exp. 2001;62:236-253.,硝苯地平,控释片,络活喜,非洛地平,缓释片,维拉帕米,缓释片,硝苯地平,控释片,络活喜,非洛地平,缓释片,维拉帕米,缓释片,清晨血压上升速度,mmHg/H,治疗前 治疗后,*,P0.05,*,*,收缩压,舒张压,交感神经兴奋增加心血管事件危险,理想的抗高血压治疗目标之一是,:,降压同时,不产生反射性交感神经系统兴奋,从而减少心血管并发症和降压治疗不良反应,Guido Grassi Current Pharmaceutical Design, 2004, 10, 3579-3589.,交感神经,系统兴奋,心输出量,高血压,动脉扩张性,组织灌注,心率,外周血管阻力,动脉粥样硬化,心律失常,左室肥厚,心肌缺血,参考文献：,Packer M, et al. N,Engl,J Med. 1996; 335:1107-14,PRAISE,研究,射血分数,30%,的重度心衰患者，对交感神经兴奋非常敏感,络活喜,未增加事件发生率和死亡率,络活喜,平稳降压,不引起反射性交感神经兴奋增强,络活喜,是,FDA,唯一批准可用于心衰患者的,CCB,降低血压是抗高血压治疗获益的关键，亚洲人群严格控制血压获益可能更大,CCB,降压治疗在脑卒中的预防上具有一定优势，应作为中国高血压患者的基础性用药。,有试验证据显示，不同,DHP-CCB,之间预防心肌梗死及冠心病事件的作用可能存在很大差异。氨氯地平比其它,DHP-CCB,有一定的优势。,对大多数高血压患者，以氨氯地平为基础必要时联合,ACEI,（,ARB,）是较理想的联合用药方案,总结,谢谢,