1、钙拮抗剂治疗高血压重要临床试验回顾,高血压治疗研究进程,1960s能否有效降低血压1970s降压能否改善患者预后1980s老年人群降压是否有益1990s各类降压药对预后影响有无差异,有关钙拮抗剂的重要临床试验,Syst-Eur Syst-China STONE HOT STOP-2 INSIGHT NORDIL,达到终点的患者比例,0 1 2 3 4 5 6 随机后的时间(年),STOP-2研究中各组达到终点的患者比例,危险患者钙拮抗剂 2196 21562094202919501422376ACEI 22052159 2104 2042 19581405352传统药物 2213 2163 2
2、118 2057 19791426368,SYOPH2，Lancet. 1999; 354:1751.,INSIGHT试验,临床预后：所有终点*的发生率,*包括所有主要终点以及非心脑血管性死亡、肾衰、心绞痛和短暂性脑缺血,患者百分数%,P=0.62,12.1,12.5,硝苯地平控释片 利尿剂联合用药,NORDIL(the Nordic Diltiazem Study),地尔硫卓、利尿剂和B-阻滞剂组均可显著降低血压(分别降低20.3/18.7mmHg，23.3/18.7 mmHg，收缩压差异P1000病人年1995年7月前尚未发表试验的主要结果,入选的临床试验(一),简称病例数 对象计划随访(
3、年)完成AASK1200HBP+Renal (disease)52001ABCD950Diabetes51998ALLHAT40000HBP+CVD (risk)62002ANBP26000HBP 52002ASCOT18000HBP+CVD(risk)52003BENEDICT2400Diabetes32001CAPPP10800HBP 51998CONVINCE15000HBP+CVD (risk)52001CSGTEI1650Diabetes+proteinuria 32000DIAB-HYCAR4000Diabetes+proteinuria 31999,入选的临床试验(二),简称病例
4、数对象计划随访(年)完成ELSA2251HBP 42000HDS1148HBP+Diabetes 8.21998HOPE9541CVD (risk)4.72000HOT19196HBP 3.51997HYVET2100HBP 52001INSIGHT6592HBP+CVD (risk) 31999LIFE9194HBP+LVH 42001NICE-EH1000HBP 51997NORDIL11000HBP 52002PART2617Atherosclerosis 41998PHYLLIS450CIT 32000,入选的临床试验(三),简称病例数对象计划随访(年)完成PREVENT285ACHD
5、51997PROGRESS6000 Stroke or TIA52000QUIET1750ACHD31996RENAAL1500Diabetes42002SCOPE4000HBP2.52003SHELL4800 HBP3.51999STOP-26628HBP41998SYST-EUR4695ISH1.61997VHAS1414HBP21996,BPLT协作研究一级终点,总死亡率CVD死亡率CVD事件 (脑卒中、CHD事件、心力衰竭和CVD死亡)脑卒中心肌梗死和CHD死亡心力衰竭 (死亡或住院),By 2003, the available data should provide good po
6、wer to detect modest differences in the incidence of each of the principal outcomes for the main treatment comparisons.By 1999, however, the power to assess such cause-specific treatment effects is likely to be suboptimal, so the principal focus of analyses at that time will be the combined outcome
7、of total cardiovascular events.,J Hypertens 1998;16:127-137,BPLT协作研究第一轮分析入选的临床试验,降压药与安慰剂比较HOPE，PART2，QUIET，SCAT，PREVENT，SYST-EUR不同降压目标值比较ABCD，HOT，UKPDS-HDS不同降压药物比较CAPPP，STOP-2，UKPDS-HDS，INSIGHT，NICE-EH，NORDIL， VHAS，ABCD,相对危险计算,BPLT协作研究第一轮分析结果(一),ACEIs CCBs 利尿剂或b阻滞剂总死亡率0.84(0.76-0.94)0.87(0.70-1.09)0
8、.87CVD死亡率0.74(0.64-0.85)0.72(0.52-0.98)0.79CVD事件0.79(0.73-0.86)0.72(0.59-0.87)Stroke0.70(0.57-0.85)0.61(0.44-0.85)0.61CHD0.80(0.72-0.89)0.79(0.59-1.06)0.84CHF0.84(0.68-1.04)0.72(0.48-1.07),与安慰剂作比较(RR),ACEI PlaceboRelative risk(95% CI) Major cardiovascular eventsHOPE726/4645919/46520.79(0.72-0.86)PAR
9、T233/30840/3090.83(0.54-1.28)QUIET49/87855/8720.88(0.61-1.29)SCAT12/22926/2310.47(0.24-0.90)Overall820/60601040/60640.79(0.73-0.86)(p homog=0.81)Cardiovascular death HOPE282/4645377/46520.75(0.72-0.91)PART28/30818/3090.45(0.20-1.01)QUIET13/87814/8720.92(0.44-1.95)SCAT4/2297/2310.58(0.17-1.94)Overall
10、307/6060416/60640.74(0.7264-0.85)(p homog=0.57)Total mortalityHOPE482/4645569/46520.85(0.76-0.95)PART216/30825/3090.64(0.35-1.18)QUIET27/87827/8720.99(0.59-1.68)SCAT8/22911/2310.73(0.30-1.79)Overall533/6060632/60640.84(0.76-0.94)(p homog=0.74),Comparisons of ACE-inhibitor-based therapy with placebo,
11、Number of events/total patients,Relative riskFavorsFavorsACE-Iplacebo,BPLT: Lancet 2000; 355:1955,0.51.02.0,Calcium PlaceboRelative riskantagonistsI(95% CI)Major cardiovascular eventsPREVENT24/41730/4080.78(0.47-1.32)SYST-EUR142/2398192/22970.71(0.57-0.87)Overall166/2815222/27050.72(0.59-0.87)(p hom
12、og=0.73)Cardiovascular death PREVENT2/4177/4080.28(0.06-1.34)SYST-EUR64/239882/22970.75(0.54-1.03)Overall66/281589/27050.72(0.52-0.98)(p homog=0.23)Total mortalltyPREVENT6/4178/4080.73(0.26-2.10)SYST-EUR135/2398147/22970.88(0.70-1.10)Overall141/2815155/27050.87(0.70-1.09)(p homog=0.74),Number of eve
13、nts/total patients,Comparisons of calcium-antagonist-based therapy with placebo,BPLT: Lancet 2000; 355:1955,0.51.02.0,Relative riskFavorsFavorscaciumplaceboantagonists,BPLT协作研究第一轮分析结果(二),积极降压的RR总死亡率0.97(0.85-1.11)CVD死亡率0.90(0.75-1.09)CVD事件0.85(0.76-0.96)Stroke0.80(0.65-0.98)CHD0.81(0.67-0.98)CHF0.78
14、(0.53-1.15),More LessRelative riskintensiveintensive(95% CI)Major cardiovascular eventsABCD36/23738/2330.91(0.60-1.37)HOT228/6262486/125280.94(0.80-1.10)UKPDS-HDS141/758105/3900.69(0.55-0.86)Overall405/7257630/131510.85(0.76-0.96)(p homog=0.08)Cardiovascular deathABCD6/23711/2330.54(0.20-1.43)HOT96/
15、6262177/125281.09(0.85-1.39)UKPDS-HDS80/75858/3900.71(0.52-0.97)Overall182/7257246/131510.90(0.75-1.09)(p homog=0.07)Total mortalltyABCD10/23722/2330.45(0.22-0.92)HOT207/6262382/125281.08(0.92-1.28)UKPDS-HDS134/75883/3900.83(0.65-1.06)Overall351/7257487/131510.97(0.85-1.11)(p homog=0.02),Number of e
16、vents/total patients,Comparisons of more intersive blood pressure lowering strategieswith less intensive strategies,BPLT: Lancet 2000; 355:1955,0.51.02.0,Relative riskFavorsFavorsmorelessintensiveintensive,ACEIsCCBs ACEIs利尿剂或b阻滞剂利尿剂或b阻滞剂CCBs总死亡率1.03(0.93-1.14)1.01(0.92-1.11)1.03(0.91-1.18)CVD死亡率1.00
17、(0.87-1.15)1.05(0.92-1.20)1.04(0.87-1.24)CVD事件1.00(0.93-1.08)1.02(0.95-1.10)0.92(0.83-1.01)Stroke1.05(0.92-1.19)0.87(0.77-0.98)1.02(0.85-1.21)CHD1.00(0.88-1.14)1.12(1.00-1.26)0.81(0.68-0.97)CHF0.92(0.77-1.09)1.12(0.95-1.33)0.82(0.67-1.00),BPLT协作研究第一轮分析结果(三)不同类型降压药作比较(RR),ACE-IDiuretio orRelative ris
18、kb-blocker(95% CI)Major oardlovascular eventsSTOP-2531/2205568/22130.94(0.85-1.04)UKPDS-HDS81/40060/3581.21(0.89-1.63)Subtotal612/2605628/25710.96(0.87-1.06)(p homog=0.12)CAPPP406/5492376/54931.08(0.94-1.24)Overall1018/80971004/80641.00(0.93-1.08)(p homog=0.12)Cardiovascular deathSTOP-2226/2205221/2
19、2131.03(0.86-1.22)UKPDS-HDS48/40032/3581.34(0.88-2.05)Subtotal274/2605253/25711.07(0.91-1.26)(p homog=0.25)CAPPP76/549295/54931.08(0.59-1.08)Overall350/8097348/80641.00(0.87-1.15)(p homog=0.13)Total mortalitySTOP-2380/2205369/22131.03(0.91-1.18)UKPDS-HDS75/40059/3581.14(0.83-1.55)Subtotal455/2605428
20、/25711.05(0.93-1.18)(p homog=0.58)CAPPP184/5492190/54930.97(0.79-1.18)Overall639/8097618/80641.03(0.93-1.14)(p homog=0.68),Number of events/total patients,0.51.02.0,BPLT: Lancet 2000; 355:1955,ACE-1 CaiciumRelative riskantagonists(95% CI)Major cardiovascular eventsABCD28/23547/2350.60(0.39-0.92)STOP
21、-2531/2205562/21960.94(0.85-1.04)Overall559/2440619/24310.92(0.83-1.01)(p homog=0.04)Cardiovascular deathABCD6/23511/2350.55(0.21-1.45)STOP-2226/2205212/21961.06(0.89-1.27)Overall232/2440223/24311.04(0.87-1.24)(p homog=0.19)Total mortalltyABCD14/23518/2350.78(0.40-1.53)STOP-2380/2205362/21961.05(0.9
22、2-1.19)Overall394/2440380/24311.03(0.91-1.18)(p homog=0.40),Number of events/total patients,Comparisons of ACE-inhibitor-based therapywith calcium-antagonist-based therapy,BPLT: Lancet 2000; 355:1955,0.51.02.0,Relative riskFavorsFavorsACE-1calciumantagonists,BPLT协作研究第一轮分析的结论,证实ACEIs和长效CCBs降压治疗能显著减少C
23、VD事件发生与CVD死亡率积极降压治疗对减少CVD事件发生能增加益处相对于降压治疗获得的益处，不同类型降压药为基础治疗方案之间的差别较小,BPLT协作研究第一轮分析的局限性,入选的临床试验数、病例数和事件数尚未达到作出肯定结论的条件，尤其在评价不同类型降压药对终点事件影响的差别时不同临床试验的样本量相差很大，其中HOPE、SYST-EUR、HOT、STOP-2等试验的结果起了决定性影响，而这些临床试验的对象和设计是特定的大部分入选的临床试验在治疗过程中有较高的失随访率(30%)，可能对意向治疗分析(ITT)的结果造成偏差,Projected Numbers of Subjects 2000 B
24、ased on Current Collaborating Studies,The role of blood pressure itself becomes predominant athigh blood pressure levels but is less important whenpressure is lower and non-pressure-dependentmechanisms become of greater importance. The curvesare hypothetical.,降压治疗试验终点事件比较(/1000病人年),汇萃分析 HOT 1990年 19
25、94年脑卒中 4.2 3.2 4.4心肌梗死 3.0 7.25 7.8CVD死亡 3.8 5.3 6.5 总死亡 8.3 9.6 12.3,血压控制目标值,高血压患者140/90 mmHg糖尿病患者130/85 mmHg,影响降压药物选择的主要因素,社会经济状况具体患者的心脑血管病危险因素状况是否有TOD和ACC是否有限制某类降压药使用的合并症患者的降压疗效与其它药物相互作用临床试验获得的证据强度,HOT Study - 需要多少药物控制血压,Hansson et al. Lancet 1998; 351:1756,2个及以上药物(69%),1个药物(31%),Combination ther
26、apy needed to achievetarget blood pressure,Monotherapy,Combinationtherapy,59%,32%,SBP/DBPmm Hg,161/98,142/83,SBP/DBPmm Hg,140/81,26%,80 mm Hg,142/83,32%,85 mm Hg,144/85,37%,90 mm Hg,Enrolment,Final,Hansson et al 1998,UKPDS 需要多少药物控制血压,UKPDS 38. BMJ 1998; 317:703-713,1个药物(29%),2 个药物(44%), 3个以上(27%),0
27、或 1 (69%),2 个药物(23%),Less tight control,Tight control, 3 个以上(8%),Control of Hypertension% Patients With BP Controlled,27%,22%,20.5%,20%,19%,USA12,Canada14,Finland16,Spain16,Australia16,140/90 mm Hg,65 yr only,12. JNC VI. Joint National Committee on Prevention, Detection,Evaluation,and Treatment of H
28、igh Blood Pressure.Arch Intern Med 1997;157:241313.Colhoun et al. J Hypertens 1998;16:747,14.Joffres et al. Am J Hypertens 1997;10:109715.Chamontin et al. Am J Hypertens 1998;11(6 Pt 1):75916.Marques-Vidal et al. J Hum Hypertons 1997;11:213 Adapted from G Mancia,Over target DBP63%,On or below target
29、 DBP37%,Based on 11,613 patients in UK, France, Germany, Italy and SpainPatients were treated with diuretics, calcium antagonists, beta-blockers and ACEinhibitors (Plain and Combined). Excluded are those whose hypertension wasdiagnosed at last consultation, those who just began treatment and those w
30、hoseblood pressure difference was not stated. (Copyright 1992 CardoMonitor, TaylorNelson Healthcare),The percentage of treated hypertensive patients with DBP over,and on or below target as set by the physician(3),Awareness(%)Treatment(%)Control(%) 78% 69% 30%,Survey of Awareness, Treatment and Contr
31、ol of Hypertension in Clinical outpatient(1999,9400 cases),上海瑞金医院门诊患者高血压现状调查（1999年）,1,2,3,5,7,10,14,0,5,10,15,20,25,30,10,20,30,40,50,60,80,MRC I,MRC II,Aust,SHEP,SWPHE,Coope,STOP,MRC I,MRC II,Aust,SHEP,EWPHE,Coope,STOP,相对益处(% 降低卒中),绝对益处(预防的卒中/千病人年),安慰剂组卒中发生率(事件/千病人年),脑卒中与心肌梗死发病率比较(每1000人年),脑卒中心肌梗死S
32、yst-Eur13.78.0Syst-China20.82.4,脑卒中/心肌梗死发病率比值,STONE8.0Syst-China8.7NICS-EH4.0SHEP1.2MRC II0.8STOP-H1.2Syst-Eur1.7,Stroke Calcium antagonist vs. diuretic/-blocker,Risk factor clustering with hypertension,ages 18 to 74 years.Framingham offspring,Am J Hypertens 2000;13:3s,HOT 心血管危险因素研究血压水平以外的各项因素对CVD发生
33、率的影响,Risk factor CV/1000 pt.yRRCl(95%)YesNoGender(M vs F)12.07.21.62(1.421.94)Age(65 vs 65 yrs)15.07.32.06(1.772.39)Smoking 14.08.91.57(1.311.88)S-Cholesterol(6.8 vs 6.8 mmol/l) 11.69.01.29(1.091.53) S-Creatinine(1.3 vs 1.3 mg/dl) 21.88.72.50(2.033.07) Diabetes 18.39.02.03(1.652.51) Ischemic Heart Disease 18.48.12.27(1.932.68),结论和思考,抗高血压临床试验已经提供了降压治疗有益以及如何获得较大益处的证据，但仍需要在特殊人群中提供更多的证据重要的问题是如何将临床试验的证据实施到临床实践和人群防治中,
