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1、联合降压药物治疗及其药物选择 钙拮抗剂的价值,李 勇 复旦大学附属华山医院心脏科 上海 200040,P for heterogeneity = 0.002,澳洲,亚洲,Hazard ratio,+10 mmHg: 1.22 (1.18-1.26),+10 mmHg: 1.31 (1.26-1.35),Mean usual SBP (mmHgl),收缩压与冠心病事件,收缩压与致死及非致死缺血性卒中,P for heterogeneity = 0.001,澳洲,亚洲,+10 mmHg: 1.24 (1.15-1.35),+10 mmHg: 1.53 (1.48-1.59),0,30,60,90,
2、120,150,1985,1990,1995,2000,2005,2010 (年),脑血管病,冠心病,标化死亡率(1/10万),CV死亡率呈上升趋势 CHD为第二位CV死因,冠心病: 中国人群死亡重要原因,在中国，高血压是冠心病的重要危险因素 高血压导致心血管病的相对危险高达3-4倍 在总的CV事件中，23.7%的急性冠心病事件归因于高血压,CHD死亡 48%,中国心血管病报告2005,2004年城市居民CHD死亡 占所有心脏病死亡的48%,Stroke and MI in Hypertension Trials,1. Kjeldsen SE et al. Blood Pressure 200
3、1;10:190-192. 2. Dalhf B et al. Lancet 2002;359:995-1003. 3. Wing LMH et al. N Engl J Med 2003;348:583-592.,5,0,1,2,3,4,5,6,7,8,STOP-1,SHEP,STONE,SYST-EUR,SYST-CHINA,HOT,CAPPP,STOP-2,NICS,NORDIL,INSIGHT,Percentage of patients with event,Stroke,Myocardial Infarction,Percentage of fatal and nonfatal s
4、trokes, and fatal and nonfatal MIs reported in large, prospective hypertension trials published after 1990.,LIFE,ANBP2,高血压患者 脑卒中/心肌梗死发病率,STONE 8.0 Syst-China 8.7 NICS-EH 4.0 SHEP 1.2 MRC II 0.8 STOP-II 1.2 Syst-Eur 1.7,抗高血压治疗效果,%降低,MacMahon SW et al. Prog Cardiovasc Dis. 1986;29(suppl 1):99118.,48%,
5、16%,脑血管疾病,冠心病,不同年龄的缺血性心脏病风险与血压关系,Lewington et al. Lancet. 2002;360:1903-1913.,Lower Is Better,至少将血压降至 SBP 140mmHg 和 DBP 90mmHg 对糖尿病患者 SBP 130mmHg 和 DBP 80mmHg 对老年人SBP 150mmHg和 DBP 90mmHg 仍然强调严格控制血压,降压治疗的目标,中国高血压指南2004,高血压药物治疗的目的,减少总的心血管病死率和病残率，而不仅仅是降低血压,抗高血压治疗的策略 降压达标是手段，靶器官保护是关键,治疗后血压水平与冠心病进展,Sipah
6、i I, et al. JACC Vol. 48, No. 4, 2006,BP Differences of 2 mmHg Are Associated With Up to a 40% Effect on CV Risk,Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years,Lewington S et al. Lancet. 2002;360:19031913.,2 mmHg decrease in mean SBP,10% reduction i
7、n risk of stroke mortality,7% reduction in risk of IHD mortality,2007ESH-ESC：及时启动药物治疗,启动药物治疗,启动药物治疗,启动药物治疗,Target BP (mm Hg),Number of antihypertensive agents,1,Trial,2,3,4,Multiple Antihypertensive Agents Are Needed to Achieve Target BP,DBP, diastolic blood pressure; MAP, mean arterial pressure; SB
8、P, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ et al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-405.,2007ESH-ESC：联合治疗成为最重要的治疗策略,为了达到降压目标，大部分高血压患者需要使用一种以上的降压药物。,联合治疗被推荐可作为起始治疗，特别是2级或3级高血压患者，或总心血管风险处于高危或极高危的患者，并建议更快地调整剂量，以使病
9、人尽快达到目标血压。,治疗高血压首先必须 降压达标 降压达标的必然选择 联合抗高血压药物治疗,钙拮抗剂的临床意义,2007 ESH-ESC 高血压诊治指南 2007-06-12,利尿剂, 受体阻断剂, 受体阻断剂,ACE抑制剂,钙拮抗剂,血管紧张素受体阻断剂(ARBs),HOT研究治疗方案,*治疗二周目标血压DBP仍大于90mmHg,HOT Study Group. Lancet. 1998;351:1755-1762.,亚洲人群使用波依定血压达标率更高 (Target 90mmHg),亚洲人群使用波依定副作用更少,钙拮抗剂,特有的全面作用,血管平滑肌的刺激与收缩机理,血管平滑肌,血管平滑肌收
10、缩,细胞内信息传导途径,钙拮抗剂治疗高血压的长处,老年和低肾素活性患者有较好降压疗效,高钠摄入不影响降压疗效,非甾体类抗炎症药物不干扰降压作用,在嗜酒的患者有显著降压作用,适用于合并糖尿病、冠心病或外周血管病患者,抗动脉粥样硬化作用,降压药物强制和可能的禁忌症,与其他降压药物相比，二氢吡啶类钙拮抗剂没有任何绝对禁忌证，是临床使用中最安全的一类降压药物,联合降压治疗的药物选择,Paolo Verdecchia,et al.Hypertension 2005;46;386-392,降压药物预防脑卒中事件,B.Dahlof (Co-chair), P.Sever (Co-chair), N. Pou
11、lter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. OBrien, J. stergren, on behalf of the ASCOT Investigators,A randomised controlled trial of the prevention of CHD and other vascular events by BP and chol
12、esterol lowering in a factorial study design,Systolic and diastolic blood pressure,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,atenolol thiazide amlodipine perindopril,137.7,136.1,79.2,77.4,Mean difference 1.9,Last visit,Mean difference 2.7,SBP,DBP,163.9,1
13、64.1,94.8,94.5,86% pts on combination therapies,All-cause mortality,Number at risk Amlodipine perindopril 9639 9544 9441 9332 9167 8078 Atenolol thiazide 9618 9532 9415 9261 9085 7975,0.0,1.0,2.0,3.0,4.0,5.0,Years,0.0,2.0,4.0,6.0,8.0,10.0,HR = 0.89 (0.810.99) p = 0.0247,%,Amlodipine perindopril (No.
14、 of events 738),Atenolol thiazide (No. of events 820),CV death + MI + stroke,0.0,1.0,2.0,3.0,4.0,5.0,Years,0.0,0.0,2.0,4.0,6.0,8.0,10.0,Amlodipine perindopril (No. of events = 796),Atenolol thiazide (No. of events = 937),HR = 0.840 (0.760.92) p 0.0003,Number at risk Amlodipine perindopril 9639 9415
15、9228 9007 8778 7655 Atenolol thiazide 9618 9400 9152 8891 8629 7500,%,Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension,Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1, Eric J. Velazquez4, and Michael A. Weber5 for the ACCOMPL
16、ISH Investigators University of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine, Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Sweden3; Duke University School of Medicine, Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5,2008.04.01 57t
17、h ACC,ACCOMPLISH: Design,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,Fr
18、ee 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,Systolic Blood Pressure
19、Over Time,mm Hg,Month,5731 5387 5206 4999 4804 4285 2520 1045 5709 5377 5154 4980 4831 4286 2594 1075,Patients,*Mean values are taken at 30 months F/U visit,129.3 mmHg,130mmHg,Difference of 0.7 mmHg p0.05*,DBP: 71.1,DBP: 72.8,37.2,37.9,ACCOMPLISH: Exceptional Control Rates with Initial Combination T
20、herapy,ACEI / HCTZ N=5733,Control rate (%),CCB / ACEI N=5713,10,20,30,40,50,60,70,80,90,P0.001 at 30 months follow-up,Control defined as 140/90 mmHg,Kaplan Meier for Primary Endpoint,Cumulative event rate,HR (95% CI): 0.80 (0.72, 0.90),Time to 1st CV morbidity/mortality (days),p = 0,650,526,.0,0,0,2
21、,INTERIM RESULTS Mar 08,Primary and Other Endpoints,Composite CV mortality/morbidity Primary w/o revascularization Hard CV endpoint (CV death, non-fatal MI, non-fatal stroke) All cause mortality,Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat p
22、opulation),Risk Ratio (95%),0.80 (0.720.90) 0.79 (0.680.92) 0.80 (0.680.94) 0.90 (0.751.08),Favors CCB / ACEI,Favors ACEI / HCTZ,INTERIM RESULTS Mar 08,降低脑卒中危险, 络活喜显著优于其他降压药物,Franz H. Messerli et al. Hypertension. 2006;48:359-361.,降低冠心病事件, 络活喜和ACEI类似,Franz H. Messerli et al. Hypertension. 2006;48:35
23、9-361.,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,William J. Elliott et al. Circulation 2006;113:2763-2772,ACTION:降压疗效,血压变化 (mmHg)
24、 高血压亚组 正常血压亚组 拜新同 -14.5/-7.0 +1.9/-0.5 安慰剂 -7.9/-3.5 +5.8/+1.9 拜新同的作用 -6.9/-3.5 -3.9/-2.4,The Covalent Group, Inc.,CAMELOT结果血压资料,Months After Randomization,Nissen et al, for the CAMELOT investigators. JAMA. 2004;292:2217-2226.,Norvasc (amlodipine besylate),Enalapril,Placebo,Systolic Pressure (mm Hg)
25、,132,130,128,126,124,122,120,Diastolic Pressure (mm Hg),80,78,76,74,72,0,1,2,6,9,12,15,18,21,24,总体血压下降均值 络活喜组 - 4.8 / 2.5 mm Hg 依那普利 组 - 4.9 / 2.4 mm Hg 安慰剂 组 + 0.7 / 0.6 mm Hg,络活喜组和依那普利组与安慰剂组比较，血压下降统计学差异显著(P0.001) 络活喜组与依那普利组比较，无显著性统计学差异,2007ESC/ESH高血压指南中引用络活喜的临床研究高达40次!,0,5,10,15,20,25,30,35,40,氨氯地
26、平研究,非洛地平缓释片研究,硝苯地平控释片研究,40次,8次,11次,络活喜 : 用最多的证据奠定了CCB在指南中的地位,07年欧洲高血压指南CCB临床研究引用频次,引用的氨氯地平主要研究：CAMELOT、ASCOT、VALUE、ALLHAT,IDNT,ELVERA,MARVAL,AASK等 引用的硝苯地平控释片研究：ACTION,INSIGHT等 引用的非洛地平缓释片研究：HOT, STOP-2等,氨氯地平(络活喜)：更多获益来源于 高质量的降压作用,诊室血压数值变化,氨氯地平高质量降压:更持久,VALUE研究24小时动态血压亚组研究(n=695): 络活喜控制服药后20-24小时血压,显著
27、优于缬沙坦,Ole Lederballe Pedersen et al.Journal of Hypertension 2007, 25:707712,氨氯地平高质量降压:更平稳,100%患者 T/P比值50%,72%患者 T/P比值50%,硝苯地平控释片,Zannad F et al. Am J Hypertens 1996; 9:633-643. Zanchetti A Journal of Hypertension 1994;12(Suppl8):S97-S106.,硝苯地平控释片FDA 说明书T/P比值： 收缩压：46-91% 舒张压：41-78%,氨氯地平:更好控制中心动脉压,140
28、,135,130,125,120,115,0 1.0 2.0 3.0 4.0 5.0 6.0,(年),133.9,133.2,125.5,121.2,络活喜组(n=1042),阿替洛尔组(n=1031),外周收缩压: 平均差异(AUC)=0.7(-0.4-1.7)mmHg,P=0.2,中心收缩压:平均差异(AUC)=4.3(3.3- 5.4)mmHg,P0.0001,收缩压 (mmHg),*ASCOT-CAFE研究:2199例来自5个英国ASCOT研究中心的患者,中心动脉压可评估人群为2073例:络活喜为基础的治疗方案组(n=1042)和阿替洛尔为基础的治疗方案组(n=1031)。随访4年。,
29、Williams B et al. Circulation 2006;113:1213-1225.,最大的ARB头对头研究: VALUE 络活喜利尿剂,欧洲最大的高血压研究: ASCOT 络活喜ACEI,世界最大的高血压研究 ALLHAT: 络活喜B阻滞剂/其他,氨氯地平： 不同的研究，一致的获益,最新降压方案研究: ACCOMPLISH 络活喜+ACEI,病人数,15245,42418,19257,11462,5年,4.2年,5.5年,治疗时间,3.9年,基线血压,155/88mmHg,146/84mmHg,164/95mmHg,145/95mmHg,高血压药物治疗的目的,减少总的心血管病死率和病残率，而不仅仅是降低血压,抗高血压治疗的策略,降压达标: RAS抑制剂+CCB（氨氯地平）：1+1=2,靶器官保护，减少心血管事件: RAS抑制剂+CCB（氨氯地平）：1+12,主席寄语,刘力生教授： “CLASSIC是改善中国高血压防治现状的一次试探。该建议书本着科学、公正、严谨的态度，系统阐述了苯磺酸氨氯地平的药理学特性和临床应用，并提出明确建议。”,胡大一教授： “CLASSIC将纷繁庞杂的临床研究结果升华为指导高血压治疗实践的推荐意见，将对正确使用苯磺酸氨氯地平发挥积极的指导作用。并为高血压治疗规范带来有益的深远影响。”,提高高血压控制率 刻不容缓,CLASSIC：意义深远,