聯(lián)合降壓藥物治療及其藥物選擇鈣拮抗劑的價(jià)值李勇

1、聯(lián)合降壓藥物治療及其藥物選擇鈣拮抗劑的價(jià)值,李 勇復(fù)旦大學(xué)附屬華山醫(yī)院心臟科上海 200040,P for heterogeneity = 0.002,澳洲,亞洲,Hazard ratio,+10 mmHg: 1.22 (1.18-1.26),+10 mmHg: 1.31 (1.26-1.35),Mean usual SBP (mmHgl),收縮壓與冠心病事件,收縮壓與致死及非致死缺血性卒中,P for heterogenei

2、ty = 0.001,澳洲,亞洲,+10 mmHg: 1.24 (1.15-1.35),+10 mmHg: 1.53 (1.48-1.59),,,,,,,,,,,,,,,,,,,,,,,,0,30,60,90,120,150,1985,1990,1995,2000,2005,2010 (年),,,,,,,,,,腦血管病,冠心病,標(biāo)化死亡率(1/10萬(wàn)),CV死亡率呈上升趨勢(shì)CHD為第二位CV死因,冠心病: 中國(guó)人群死亡重要原因,在中國(guó)

3、，高血壓是冠心病的重要危險(xiǎn)因素高血壓導(dǎo)致心血管病的相對(duì)危險(xiǎn)高達(dá)3-4倍在總的CV事件中，23.7%的急性冠心病事件歸因于高血壓,CHD死亡48%,《中國(guó)心血管病報(bào)告2005》,2004年城市居民CHD死亡占所有心臟病死亡的48%,Stroke and MI in Hypertension Trials,1. Kjeldsen SE et al. Blood Pressure 2001;10:190-192. 2. Dalh

4、46;f 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

5、of patients with event,,,Stroke,,Myocardial Infarction,Percentage of fatal and nonfatal strokes, and fatal and nonfatal MIs reported in large, prospective hypertension trials published after 1990.,,,,,,,,,,,,,,LIFE,,,ANB

6、P2,高血壓患者腦卒中/心肌梗死發(fā)病率,STONE8.0Syst-China8.7NICS-EH4.0SHEP1.2MRC II0.8STOP-II1.2Syst-Eur1.7,抗高血壓治療效果,%降低,MacMahon SW et al. Prog Cardiovasc Dis. 1986;29(suppl 1):99–118.,,,,,,,,,,48%,16%,腦血管疾病,冠心病,,不同年齡的缺血性心臟病

7、風(fēng)險(xiǎn)與血壓關(guān)系,Lewington et al. Lancet. 2002;360:1903-1913.,Lower Is Better,至少將血壓降至 SBP < 140mmHg 和 DBP < 90mmHg 對(duì)糖尿病患者 SBP < 130mmHg 和 DBP < 80mmHg 對(duì)老年人SBP < 150mmHg和 DBP < 90mmHg 仍然強(qiáng)調(diào)嚴(yán)格控制血壓,降壓治療的目標(biāo),中

8、國(guó)高血壓指南2004,高血壓藥物治療的目的,減少總的心血管病死率和病殘率，而不僅僅是降低血壓,抗高血壓治療的策略降壓達(dá)標(biāo)是手段，靶器官保護(hù)是關(guān)鍵,治療后血壓水平與冠心病進(jìn)展,Sipahi 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-analys

9、is of 61 prospective, observational studies1 million adults12.7 million person-years,Lewington S et al. Lancet. 2002;360:1903–1913.,,,,2 mmHg decrease in mean SBP,10% reduction in risk of stroke mortality,7% reduction

10、in risk of IHD mortality,,,,2007ESH-ESC：及時(shí)啟動(dòng)藥物治療,啟動(dòng)藥物治療,啟動(dòng)藥物治療,啟動(dòng)藥物治療,,Target BP (mm Hg),Number of antihypertensive agents,,1,Trial,,,,2,,3,,4,,,Multiple Antihypertensive Agents Are Needed to Achieve Target BP,DBP, dias

11、tolic blood pressure; MAP, mean arterial pressure; SBP, 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. 200

12、2;4:393-405.,2007ESH-ESC：聯(lián)合治療成為最重要的治療策略,為了達(dá)到降壓目標(biāo)，大部分高血壓患者需要使用一種以上的降壓藥物。,聯(lián)合治療被推薦可作為起始治療，特別是2級(jí)或3級(jí)高血壓患者，或總心血管風(fēng)險(xiǎn)處于高?；驑O高危的患者，并建議更快地調(diào)整劑量，以使病人盡快達(dá)到目標(biāo)血壓。,治療高血壓首先必須降壓達(dá)標(biāo)降壓達(dá)標(biāo)的必然選擇聯(lián)合抗高血壓藥物治療,,鈣拮抗劑的臨床意義,,2007 ESH-ESC 高血壓診治指南200

13、7-06-12,,,,,,,,,,,,利尿劑,? 受體阻斷劑,? 受體阻斷劑,ACE抑制劑,鈣拮抗劑,血管緊張素受體阻斷劑(ARBs),,,,,HOT研究治療方案,*治療二周目標(biāo)血壓DBP仍大于90mmHg,HOT Study Group. Lancet. 1998;351:1755-1762.,,亞洲人群使用波依定血壓達(dá)標(biāo)率更高 (Target < 90mmHg),亞洲人群使用波依定副作用更少,,,鈣拮抗劑,特有的全面作用,血

14、管平滑肌的刺激與收縮機(jī)理,血管平滑肌,血管平滑肌收縮,細(xì)胞內(nèi)信息傳導(dǎo)途徑,鈣拮抗劑治療高血壓的長(zhǎng)處,老年和低腎素活性患者有較好降壓療效,,高鈉攝入不影響降壓療效,非甾體類(lèi)抗炎癥藥物不干擾降壓作用,在嗜酒的患者有顯著降壓作用,適用于合并糖尿病、冠心病或外周血管病患者,抗動(dòng)脈粥樣硬化作用,降壓藥物強(qiáng)制和可能的禁忌癥,,,與其他降壓藥物相比，二氫吡啶類(lèi)鈣拮抗劑沒(méi)有任何絕對(duì)禁忌證，是臨床使用中最安全的一類(lèi)降壓藥物,聯(lián)合降壓治療的藥物選擇,,Pa

15、olo Verdecchia,et al.Hypertension 2005;46;386-392,降壓藥物預(yù)防腦卒中事件,,,,,,,B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. CollinsS. Kjeldsen, A. Kristinss

16、on, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators,A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering

17、 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 ?

18、thiazide amlodipine ? perindopril,,,137.7,136.1,79.2,77.4,Mean difference 1.9,,,,,,,Last visit,Mean difference 2.7,SBP,DBP,,,,,,,163.9,164.1,,,94.8,94.5,86% pts on combination therapies,All-cause mortality,,,,,,Number

19、at riskAmlodipine ? perindopril 96399544 9441 93329167 8078Atenolol ? thiazide 96189532 9415 92619085 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 = 0.02

20、47,%,Amlodipine ? perindopril(No. 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

21、(No. of events = 796),Atenolol ? thiazide(No. of events = 937),HR = 0.840 (0.76­0.92)p < 0.0003,Number at riskAmlodipine ? perindopril 96399415 9228 90078778 7655Atenolol ? thiazide 96189400 9152 8

22、8918629 7500,%,,Avoiding Cardiovascular Events throughCOMbination Therapy in Patients LIving with Systolic Hypertension,Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1, Eric J. Velazquez4, and Mic

23、hael A. Weber5 for the ACCOMPLISH InvestigatorsUniversity of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine, Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Swed

24、en3; Duke University School of Medicine, Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5,2008.04.01 57th ACC,ACCOMPLISH: Design,Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A,*Beta blockers; alpha bloc

25、kers; 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 a

26、dd-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 BP<140/90 mmHg;

27、<130/80 mmHg in patients with diabetes or renal insufficiency,Systolic Blood Pressure Over Time,mm Hg,Month,5731538752064999480442852520104557095377515449804831428625941075,Patients,*Mean values are tak

28、en at 30 months F/U visit,129.3 mmHg,130mmHg,Difference of 0.7 mmHg p<0.05*,,DBP: 71.1,,DBP: 72.8,37.2,37.9,ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy,ACEI / HCTZN=5733,Control rate (%),,

29、,,,CCB / ACEIN=5713,,,,,,,,,10,20,30,40,50,60,70,80,90,,,,,P<0.001 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

30、 to 1st CV morbidity/mortality (days),p = 0,650,526,.0,0,0,2,INTERIM RESULTS Mar 08,,Primary and Other Endpoints,Composite CV mortality/morbidityPrimary w/o revascularizationHard CV endpoint(CV death, non-fatal MI, no

31、n-fatal stroke)All cause mortality,Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008(Intent-to-treat population),Risk Ratio(95%),0.80 (0.72–0.90)0.79 (0.68–0.92)0.80 (0.68–0.94)

32、0.90 (0.75–1.08),,Favors CCB / ACEI,Favors ACEI / HCTZ,INTERIM RESULTS Mar 08,降低腦卒中危險(xiǎn),絡(luò)活喜®顯著優(yōu)于其他降壓藥物,Franz H. Messerli et al. Hypertension. 2006;48:359-361.,降低冠心病事件,絡(luò)活喜®和ACEI類(lèi)似,Franz H. Messerli et al. Hyp

33、ertension. 2006;48:359-361.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,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,C

34、CB與對(duì)照藥物收縮壓差值 (mm Hg),-5 0 5,,10 15,0.50,0.75,1.00,1.25,1.50,,,氨氯地平的臨床研究均符合降低血壓減少冠心病事件的規(guī)律,,,William J. Elliott et al. Circulation 2006;113:2763-277

35、2,,ACTION:降壓療效,血壓變化 (mmHg)高血壓亞組正常血壓亞組拜新同-14.5/-7.0+1.9/-0.5安慰劑 -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結(jié)果—血壓資料,Months After Randomization,Nissen et al, for

36、 the CAMELOT investigators. JAMA. 2004;292:2217-2226.,Norvasc® (amlodipine besylate),Enalapril,Placebo,,,,Systolic Pressure (mm Hg),132,130,128,126,124,122,120,,,,,,,,,,,,,,,,,Diastolic Pressure (mm Hg),80,78,76,74,

37、72,0,1,2,6,9,12,15,18,21,24,,,,總體血壓下降均值絡(luò)活喜組 - 4.8 / 2.5 mm Hg依那普利組 - 4.9 / 2.4 mm Hg安慰劑組 + 0.7 / 0.6 mm Hg,絡(luò)活喜組和依那普利組與安慰劑組比較，血壓下降統(tǒng)計(jì)學(xué)差異顯著(P<0.001)絡(luò)活喜組與依那普利組比較，無(wú)顯著性統(tǒng)計(jì)學(xué)差異,2007ESC/ESH高血壓指南

38、中引用絡(luò)活喜的臨床研究高達(dá)40次!,,,,,,,,,,,,,,,,,,,0,5,10,15,20,25,30,35,40,氨氯地平研究,非洛地平緩釋片研究,硝苯地平控釋片研究,40次,8次,11次,絡(luò)活喜® : 用最多的證據(jù)奠定了CCB在指南中的地位,07年歐洲高血壓指南CCB臨床研究引用頻次,引用的氨氯地平主要研究：CAMELOT、ASCOT、VALUE、ALLHAT,IDNT,ELVERA,MARVAL,AASK等引用的

39、硝苯地平控釋片研究：ACTION,INSIGHT等引用的非洛地平緩釋片研究：HOT, STOP-2等,,氨氯地平(絡(luò)活喜)：更多獲益來(lái)源于高質(zhì)量的降壓作用,診室血壓數(shù)值變化,氨氯地平高質(zhì)量降壓:更持久,VALUE研究24小時(shí)動(dòng)態(tài)血壓亞組研究(n=695):絡(luò)活喜®控制服藥后20-24小時(shí)血壓,顯著優(yōu)于纈沙坦,Ole Lederballe Pedersen et al.Journal of Hypertension 200

40、7, 25:707–712,氨氯地平高質(zhì)量降壓:更平穩(wěn),,,,,100%患者T/P比值>50%,,,,,,,72%患者T/P比值>50%,,硝苯地平控釋片,Zannad F et al. Am J Hypertens 1996; 9:633-643.Zanchetti A Journal of Hypertension 1994;12(Suppl8):S97-S106.,硝苯地平控釋片F(xiàn)DA 說(shuō)明書(shū)T/P比值：收縮壓

41、：46-91%舒張壓：41-78%,氨氯地平:更好控制中心動(dòng)脈壓,,140,135,130,125,120,115,,,,,,,,,,,,,0 1.0 2.0 3.0 4.0 5.0 6.0,(年),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

42、,,,,,,,,,,,,,,,,133.9,133.2,125.5,121.2,,,,,,絡(luò)活喜®組(n=1042),阿替洛爾組(n=1031),,,,,外周收縮壓: 平均差異(AUC)=0.7(-0.4-1.7)mmHg,P=0.2,中心收縮壓:平均差異(AUC)=4.3(3.3- 5.4)mmHg,P<0.0001,收縮壓 (mmHg),*ASCOT-CAFE研究:2199例來(lái)自5個(gè)英國(guó)ASCOT研究中心的患者,中心

43、動(dòng)脈壓可評(píng)估人群為2073例:絡(luò)活喜為基礎(chǔ)的治療方案組(n=1042)和阿替洛爾為基礎(chǔ)的治療方案組(n=1031)。隨訪4年。,Williams B et al. Circulation 2006;113:1213-1225.,,,,最大的ARB頭對(duì)頭研究: VALUE絡(luò)活喜±利尿劑,歐洲最大的高血壓研究: ASCOT絡(luò)活喜±ACEI,世界最大的高血壓研究ALLHAT:絡(luò)活喜±B阻滯劑/其他,氨氯地

44、平： 不同的研究，一致的獲益,,最新降壓方案研究: ACCOMPLISH絡(luò)活喜+ACEI,病人數(shù),15245,42418,19257,11462,5年,4.2年,5.5年,治療時(shí)間,3.9年,,基線血壓,155/88mmHg,146/84mmHg,164/95mmHg,145/95mmHg,高血壓藥物治療的目的,減少總的心血管病死率和病殘率，而不僅僅是降低血壓,抗高血壓治療的策略,降壓達(dá)標(biāo): RAS抑制劑+CCB（氨氯地平）：1

45、+1=2,靶器官保護(hù)，減少心血管事件:RAS抑制劑+CCB（氨氯地平）：1+1>2,,,主席寄語(yǔ),,劉力生教授： “CLASSIC是改善中國(guó)高血壓防治現(xiàn)狀的一次試探。該建議書(shū)本著科學(xué)、公正、嚴(yán)謹(jǐn)?shù)膽B(tài)度，系統(tǒng)闡述了苯磺酸氨氯地平的藥理學(xué)特性和臨床應(yīng)用，并提出明確建議?！?,,胡大一教授： “CLASSIC將紛繁龐雜的臨床研究結(jié)果升華為指導(dǎo)高血壓治療實(shí)踐的推薦意見(jiàn)，將對(duì)正確使用苯磺酸氨氯地平發(fā)揮積極的指導(dǎo)作用。