鈣拮抗劑治療高血壓重要臨床試驗(yàn)回顧

1、高血壓治療研究進(jìn)程1960s能否有效降低血壓1970s降壓能否改善患者預(yù)后1980s老年人群降壓是否有益1990s各類降壓藥對(duì)預(yù)后影響有無差異有關(guān)鈣拮抗劑的重要臨床試驗(yàn) Syst-Eur Syst-China STONE HOT STOP-2 INSIGHT NORDIL達(dá)到終點(diǎn)的患者比例0 1 2 3 4 5 6 隨機(jī)后的時(shí)間(年)STOP-2研究中各組達(dá)到終點(diǎn)的患者比例危險(xiǎn)患者鈣拮抗劑 2196 21562094202919501422376ACEI 22052159 2104 2042 19581405352傳統(tǒng)藥物 2213 2163 2118 2057 19791426368 SYO

2、PH2，Lancet. 1999; 354:1751.INSIGHT試驗(yàn)臨床預(yù)后：所有終點(diǎn)*的發(fā)生率*包括所有主要終點(diǎn)以及非心腦血管性死亡、腎衰、心絞痛和短暫性腦缺血患者百分?jǐn)?shù)%硝苯地平控釋片 利尿劑聯(lián)合用藥NORDIL(the Nordic Diltiazem Study)地爾硫卓、利尿劑和B-mmHg，23.3/18.7 mmHg，收縮壓差異P1000病人年1995年7月前尚未發(fā)表試驗(yàn)的主要結(jié)果入選的臨床試驗(yàn)(一)簡(jiǎn)稱病例數(shù) 對(duì)象計(jì)劃隨訪(年)完成AASK1200HBP+Renal (disease)52001ABCD950Diabetes51998ALLHAT40000HBP+CVD (

3、risk)62002ANBP26000HBP 52002ASCOT18000HBP+CVD(risk)52003BENEDICT2400Diabetes32001CAPPP10800HBP 51998CONVINCE15000HBP+CVD (risk)52001CSGTEI1650Diabetes+proteinuria 32000DIAB-HYCAR4000Diabetes+proteinuria 31999入選的臨床試驗(yàn)(二)簡(jiǎn)稱病例數(shù)對(duì)象計(jì)劃隨訪(年)完成ELSA2251HBP 42000HDS1148HBP+Diabetes 8.21998HOPE9541CVD (risk)4.72

4、000HOT19196HBP 3.51997HYVET2100HBP 52001INSIGHT6592HBP+CVD (risk) 31999LIFE9194HBP+LVH 42001NICE-EH1000HBP 51997NORDIL11000HBP 52002PART2617Atherosclerosis 41998PHYLLIS450CIT 32000入選的臨床試驗(yàn)(三)簡(jiǎn)稱病例數(shù)對(duì)象計(jì)劃隨訪(年)完成PREVENT285ACHD51997PROGRESS6000 Stroke or TIA52000QUIET1750ACHD31996RENAAL1500Diabetes42002SCO

5、PE4000HBP2.52003SHELL4800 HBP3.51999STOP-26628HBP41998SYST-EUR4695ISH1.61997VHAS1414HBP21996BPLT協(xié)作研究一級(jí)終點(diǎn)總死亡率CVD死亡率CVD事件 (腦卒中、CHD事件、心力衰竭和CVD死亡)腦卒中心肌梗死和CHD死亡心力衰竭 (死亡或住院)By 2003, the available data should provide good power to detect modest differences in the incidence of each of the principal outcomes

6、 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 of total cardiovascular events.J Hypertens 1998;16:127-137BPLT協(xié)作研究第一輪分析入選的臨床試驗(yàn)降壓藥與安

7、慰劑比較HOPE，PART2，QUIET，SCAT，PREVENT，SYST-EUR不同降壓目標(biāo)值比較ABCD，HOT，UKPDS-HDS不同降壓藥物比較CAPPP，STOP-2，UKPDS-HDS，INSIGHT，NICE-EH，NORDIL， VHAS，ABCD相對(duì)危險(xiǎn)計(jì)算RRei / niec / ncBPLT協(xié)作研究第一輪分析結(jié)果(一)ACEIs CCBs 利尿劑或b阻滯劑CVD事件0.79(0.73-0.86)0.72(0.59-0.87)CHF0.84(0.68-1.04)0.72(0.48-1.07)與安慰劑作比較(RR)ACEI PlaceboRelative risk(95%

8、 CI) Major cardiovascular eventsHOPE726/4645919/46520.79(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)Overall820/60601040/60640.79(0.73-0.86)(p homog=0.81)Cardiovascular death HOPE282/4645377/46520.75(0.72-0.91)PART28/30818/3090.45(0.20-1.0

9、1)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)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)(

10、p homog=0.74)Comparisons of ACE-inhibitor-based therapy with placeboNumber of events/total patientsRelative riskFavorsFavorsACE-IplaceboBPLT: Lancet 2000; 355:1955Calcium PlaceboRelative riskantagonistsI(95% CI)Major cardiovascular eventsPREVENT24/41730/4080.78(0.47-1.32)SYST-EUR142/2398192/22970.71

11、(0.57-0.87)Overall166/2815222/27050.72(0.59-0.87)(p homog=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/

12、2815155/27050.87(0.70-1.09)(p homog=0.74)Number of events/total patientsComparisons of calcium-antagonist-based therapy with placeboBPLT: Lancet 2000; 355:1955Relative riskFavorsFavorscaciumplaceboantagonistsBPLT協(xié)作研究第一輪分析結(jié)果(二)積極降壓的RR總死亡率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

13、.80(0.65-0.98)CHD0.81(0.67-0.98)CHF0.78(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 dea

14、thABCD6/23711/2330.54(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)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)Overall351/7257487/131510.9

15、7(0.85-1.11)(p homog=0.02)Number of events/total patientsComparisons of more intersive blood pressure lowering strategieswith less intensive strategiesBPLT: Lancet 2000; 355:1955Relative riskFavorsFavorsmorelessintensiveintensiveACEIsCCBs ACEIs利尿劑或b阻滯劑利尿劑或b阻滯劑CCBs總死亡率1.03(0.93-1.14)1.01(0.92-1.11)1.

16、03(0.91-1.18)CVD死亡率1.00(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協(xié)作研究第一輪分析結(jié)果(三)不同類型降壓藥作比較(RR)ACE-IDi

17、uretio orRelative riskb-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 dea

18、thSTOP-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)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(0.83-1.5

19、5)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)Number of events/total patientsBPLT: Lancet 2000; 355:1955ACE-1 CaiciumRelative riskantagonists(95% CI)Major cardiovascular eventsABCD28/23547/2350.60(0.39-0

20、.92)STOP-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-2380/2205362/2196

21、1.05(0.92-1.19)Overall394/2440380/24311.03(0.91-1.18)(p homog=0.40)Number of events/total patientsComparisons of ACE-inhibitor-based therapywith calcium-antagonist-based therapyBPLT: Lancet 2000; 355:1955Relative riskFavorsFavorsACE-1calciumantagonistsBPLT協(xié)作研究第一輪分析的結(jié)論證實(shí)ACEIs和長(zhǎng)效CCBs降壓治療能顯著減少CVD事件發(fā)生與C

22、VD死亡率積極降壓治療對(duì)減少CVD事件發(fā)生能增加益處相對(duì)于降壓治療獲得的益處，不同類型降壓藥為基礎(chǔ)治療方案之間的差別較小BPLT協(xié)作研究第一輪分析的局限性入選的臨床試驗(yàn)數(shù)、病例數(shù)和事件數(shù)尚未達(dá)到作出肯定結(jié)論的條件，尤其在評(píng)價(jià)不同類型降壓藥對(duì)終點(diǎn)事件影響的差別時(shí)不同臨床試驗(yàn)的樣本量相差很大，其中HOPE、SYST-EUR、HOT、STOP-2等試驗(yàn)的結(jié)果起了決定性影響，而這些臨床試驗(yàn)的對(duì)象和設(shè)計(jì)是特定的大部分入選的臨床試驗(yàn)在治療過程中有較高的失隨訪率(30%)，可能對(duì)意向治療分析(ITT)的結(jié)果造成偏差Projected Numbers of Subjects 2000 Based on Cur

23、rent Collaborating StudiesDIAB-HYCARAASKABCDELSAEUROPAIDNTINVESTLIFEPHYLLISPROGRESSSCOPEANBP2CONVINCERENAALACTIONALLHATBENEDICTVALUEASCOTHYVETOPERAPEACEADVANCEThe role of blood pressure itself becomes predominant athigh blood pressure levels but is less important whenpressure is lower and non-pressu

24、re-dependentmechanisms become of greater importance. The curvesare hypothetical.Blood pressureNon-pressure dependent mechanismRiskPressure dependent mechanism降壓治療試驗(yàn)終點(diǎn)事件比較(/1000病人年) 匯萃分析 HOT 1990年 1994年CVD死亡 3.8 5.3 6.5 總死亡 8.3 9.6 12.3 血壓控制目標(biāo)值高血壓患者140/90 mmHg糖尿病患者130/85 mmHg影響降壓藥物選擇的主要因素社會(huì)經(jīng)濟(jì)狀況具體患者的心

25、腦血管病危險(xiǎn)因素狀況是否有TOD和ACC是否有限制某類降壓藥使用的合并癥患者的降壓療效與其它藥物相互作用臨床試驗(yàn)獲得的證據(jù)強(qiáng)度HOT Study - 需要多少藥物控制血壓Hansson et al. Lancet 1998; 351:17562個(gè)及以上藥物(69%)1個(gè)藥物(31%)Combination therapy needed to achievetarget blood pressureMonotherapyCombinationtherapy59%32%SBP/DBPmm Hg161/98142/83SBP/DBPmm Hg140/8126%80 mm Hg142/8332%85

26、mm Hg144/8537%90 mm HgEnrolmentFinalHansson et al 1998UKPDS 需要多少藥物控制血壓UKPDS 38. BMJ 1998; 317:703-7131個(gè)藥物(29%)2 個(gè)藥物(44%) 3個(gè)以上(27%)0 或 1 (69%) 2 個(gè)藥物(23%)Less tight controlTight control 3 個(gè)以上(8%)Control of Hypertension% Patients With BP Controlled27%22%20.5%20%19%USA12Canada14Finland16Spain16Australia

27、16140/90 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 Hypertens 1998;11(6 Pt 1):

28、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 (Plain and Combined). Excl

29、uded 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,and on or below target as s

30、et by the physician(3)Awareness(%)Treatment(%)Control(%) 78% 69% 30%Survey of Awareness, Treatment and Control of Hypertension in Clinical outpatient(1999,9400 cases)上海瑞金醫(yī)院門診患者高血壓現(xiàn)狀調(diào)查（1999年）年齡知曉率%治療率%控制率%35-4465.768.617.145-5479.677.816.755-6479.578.412.56582.679.811.9合計(jì)79.077.613.612357101405101520253010203040506080MRC IMRC IIAustSHEPSWPHECoopeSTOPMRC IMRC IIAustSHEPEWPHECoopeSTOP相對(duì)益處(% 降低卒中)絕對(duì)益處(預(yù)防的卒中/千病人年)安慰劑組卒中發(fā)生率(事件/千病人年)腦卒中與心肌梗死發(fā)病率比較(每1000人年)腦卒中心肌梗死腦卒中/心肌梗死發(fā)病率比值Stroke Calcium antagonist vs. diuretic/-blocker -block/diur events n Favours CA