钙拮抗剂治疗高血压重要临床试验回顾

1、钙拮抗剂治疗高血压重要临床试验回顾钙拮抗剂治疗高血压重要临床试验回顾l1960s能否有效降低血压l1970s降压能否改善患者预后l1980s老年人群降压是否有益l1990s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有关钙拮抗剂的重要临床试验 S y s t - E u r S y s t - C h i n a S T O N E H O T S T O P - 2 I N S I G H T N O R D I L051015Conventional drugsACE inhibitorsCalcium antagonists达到终点的患者比例达到终点的患者比例0 1 2 3 4

2、 5 6 随机后的时间随机后的时间(年年)危险患者钙拮抗剂 2196 21562094202919501422376ACEI 22052159 2104 2042 19581405352传统药物 2213 2163 2118 2057 19791426368 SYOPH2，Lancet. 1999; 354:1751.02468101214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=0.6212.112.5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

3、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l1995年7月前尚未发表试验的主要结果l总死亡率lCVD死亡率lCVD事件 (脑卒中、CHD事件、心力衰竭和CVD死亡)l脑卒中l心肌梗死和CHD死亡l心力衰竭 (死亡或住院)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，ABCDRRei / niec / n

4、cStroke0.70(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)ACEI PlaceboRelative risk(95% CI) HOPE726/4645919/46520.79(0.72-0.86)PART233/30840/3090.83(0.54-1.28)QUIET49/87855/8720.88(0.61-1.29)SCAT12/22926/2310.47(0.24-0.90)Overall820/60601040/60640

5、.79(0.73-0.86)(p homog=0.81)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)Overall307/6060416/60640.74(0.7264-0.85)(p homog=0.57)HOPE482/4645569/46520.85(0.76-0.95)PART216/30825/3090.64(0.35-1.18)QUIET27/87827/8720.99(0.

6、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 placeboRelative riskFavorsFavorsACE-IplaceboBPLT: Lancet 2000; 355:19550.51.02.0Calcium PlaceboRelative riskantagonistsI(95% CI)PREVENT24/41730/4080.78(0.47-1.32)

7、SYST-EUR142/2398192/22970.71(0.57-0.87)Overall166/2815222/27050.72(0.59-0.87)(p homog=0.73)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)PREVENT6/4178/4080.73(0.26-2.10)SYST-EUR135/2398147/22970.88(0.70-1.10)Overall141/2815155/

8、27050.87(0.70-1.09)(p homog=0.74)Comparisons of calcium-antagonist-based therapy with placeboBPLT: Lancet 2000; 355:19550.51.02.0Relative riskFavorsFavorscaciumplaceboantagonistsStroke0.80(0.65-0.98)CHD0.81(0.67-0.98)CHF0.78(0.53-1.15)More LessRelative riskintensiveintensive(95% CI)ABCD36/23738/2330

9、.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)ABCD6/23711/2330.54(0.20-1.43)HOT96/6262177/125281.09(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)ABCD10/

10、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)Comparisons of more intersive blood pressure lowering strategieswith less intensive strategiesBPLT: Lancet 2000; 355:19550.51.02.0Relative riskFavorsFa

11、vorsmorelessintensiveintensiveStroke1.05(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)ACE-IDiuretio orRelative riskb-blocker(95% CI)STOP-2531/2205568/22130.94(0.85-1.04)UKPDS-HDS81/40060/3581.21(0.89-1.63)Subt

12、otal612/2605628/25710.96(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)STOP-2226/2205221/22131.03(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)O

13、verall350/8097348/80641.00(0.87-1.15)(p homog=0.13)STOP-2380/2205369/22131.03(0.91-1.18)UKPDS-HDS75/40059/3581.14(0.83-1.55)Subtotal455/2605428/25711.05(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)0.51.02.0BPLT: Lancet 2000; 355:195

14、5ACE-1 CaiciumRelative riskantagonists(95% CI)ABCD28/23547/2350.60(0.39-0.92)STOP-2531/2205562/21960.94(0.85-1.04)Overall559/2440619/24310.92(0.83-1.01)(p homog=0.04)ABCD6/23511/2350.55(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)ABCD14/23518/23

15、50.78(0.40-1.53)STOP-2380/2205362/21961.05(0.92-1.19)Overall394/2440380/24311.03(0.91-1.18)(p homog=0.40)Comparisons of ACE-inhibitor-based therapywith calcium-antagonist-based therapyBPLT: Lancet 2000; 355:19550.51.02.0Relative riskFavorsFavorsACE-1calciumantagonistsl证实ACEIs和长效CCBs降压治疗能显著减少CVD事件发生与

16、CVD死亡率l积极降压治疗对减少CVD事件发生能增加益处l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l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l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l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05010015020025030020002001200220032004200520062007YearThou

17、sands of subjectsDIAB-HYCARAASKABCDELSAEUROPAIDNTINVESTLIFEPHYLLISPROGRESSSCOPEANBP2CONVINCERENAALACTIONALLHATBENEDICTVALUEASCOTHYVETOPERAPEACEADVANCEThe role of blood pressure itself becomes predominant athigh blood pressure levels but is less important whenpressure is lower and non-pressure-depend

18、entmechanisms become of greater importance. The curvesare hypothetical.Blood pressureNon-pressure dependent mechanismRiskPressure dependent mechanism 汇萃分析 HOT 1990年 1994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 q高血压患者140/90 mmHgq糖尿病患者130/85 mmHgo社会经济状况o具体患者的心脑血管病危险因素状况o是否有T

19、OD和ACCo是否有限制某类降压药使用的合并症o患者的降压疗效o与其它药物相互作用o临床试验获得的证据强度HOT Study - 需要多少药物控制血压需要多少药物控制血压Hansson et al. Lancet 1998; 351:17562个及以上药物个及以上药物(69%)1个药物个药物(31%)Combination therapy needed to achievetarget blood pressureMonotherapyCombinationtherapy59%32%SBP/DBPmm Hg161/98142/83SBP/DBPmm Hg140/8126% 80 mm Hg14

20、2/8332% 85 mm Hg144/8537% 90 mm HgEnrolmentFinalHansson et al 1998UKPDS 需要多少药物控制血压需要多少药物控制血压UKPDS 38. BMJ 1998; 317:703-7131个药物个药物(29%)2 个药物(44%) 3个以上(27%)0 或 1 (69%) 2 个药物(23%)Less tight controlTight control 3 个以上(8%)Control of Hypertension% Patients With BP Controlled27%22%20.5%20%19%USA12Canada14

21、Finland16Spain16Australia16140/90 mm Hg65 yr only12. JNC VI. Joint National Committee on Prevention, Detection,Evaluation,and Treatment of High Blood Pressure.Arch Intern Med 1997;157:241313.Colhoun et al. J Hypertens 1998;16:74714.Joffres et al. Am J Hypertens 1997;10:109715.Chamontin et al. Am J H

22、ypertens 1998;11(6 Pt 1):75916.Marques-Vidal et al. J Hum Hypertons 1997;11:213 Adapted from G ManciaOver target DBP63%On or below target DBP37%Based on 11,613 patients in UK, France, Germany, Italy and SpainPatients were treated with diuretics, calcium antagonists, beta-blockers and ACEinhibitors (

23、Plain and Combined). Excluded are those whose hypertension wasdiagnosed at last consultation, those who just began treatment and those whoseblood pressure difference was not stated. (Copyright 1992 CardoMonitor, TaylorNelson Healthcare)The percentage of treated hypertensive patients with DBP over,an

24、d on or below target as set by the physician(3)Awareness(%) Treatment(%) Control(%) 78% 69% 30%Survey of Awareness, Treatment and Control of Hypertension in Clinical outpatient(1999,9400 cases)上海瑞金医院门诊患者高血压现状调上海瑞金医院门诊患者高血压现状调查（查（1999年）年）年龄年龄知晓率知晓率%治疗率治疗率%控制率控制率%35-4435-4465.765.768.668.617.117.145-5

25、445-5479.679.677.877.816.716.755-6455-6479.579.578.478.412.512.5656582.682.679.879.811.911.9合计合计79.079.077.677.613.613.61 12 23 35 57 7101014140 05 5101015152020252530301010202030304040505060608080MRC IMRC IIAustSHEPSWPHECoopeSTOPMRC IMRC IIAustSHEPEWPHECoopeSTOP相对益处相对益处(% 降低卒中降低卒中)绝对益处绝对益处(预防的卒中预防的

26、卒中/千病人年千病人年)安慰剂组卒中发生率安慰剂组卒中发生率(事件事件/千病人年千病人年)脑卒中心肌梗死Syst-Eur13.78.0Syst-China20.82.4STONE8.0Syst-China8.7NICS-EH4.0SHEP1.2MRC II0.8STOP-H1.2Syst-Eur1.7Stroke Calcium antagonist vs. diuretic/-blocker -block/diur events n Favours CA Favours -block/diurRR (95% CI)0.51.02.0 0.94 (0.70-1.28) INSIGHT 79 3

27、157 84 3164 0.75 (0.26-2.12) NICS-EH 6 215 8 214 0.88 (0.74-1.05) STOP-2 207 2196 237 2213 0.89 (0.77-1.04) Subtotal DHP CA 0.82 (0.67-1.01) NORDIL 159 5410 196 5471 1.25 (0.34-4.64) VHAS 5 707 4 707 0.83 (0.68-1.02) Subtotal nDHP CA 0.87 (0.77-0.98) Overall (p homog=0.91) CA events nRelative RiskOn

28、e26.0%Two25.0%Three22.0%Four ormore8.0%None19.0%MenOne27.0%Two24.0%Three20.0%Four ormore12.0%None17.0%WomenRisk factor clustering with hypertension,ages 18 to 74 years.Framingham offspringAm J Hypertens 2000;13:3sRisk 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