鈣拮抗劑治療高血壓重要臨床試驗回顧

1、鈣拮抗劑治療高血壓重要臨床試驗回顧,高血壓治療研究進程,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各類降壓藥對預(yù)后影響有無差異,有關(guān)鈣拮抗劑的重要臨床試驗,Syst-Eur Syst-China STONE HOT STOP-2 INSIGHT NORDIL,達到終點的患者比例％,0 1 2

2、 3 4 5 6 隨機后的時間(年),STOP-2研究中各組達到終點的患者比例,危險患者鈣拮抗劑 2196 21562094202919501422376ACEI 22052159 2104 2042 195814

3、05352傳統(tǒng)藥物 2213 2163 2118 2057 19791426368,SYOP－H2，Lancet. 1999; 354:1751..,INSIGHT試驗,臨床預(yù)后：所有終點*的發(fā)生率,*包括所有主要終點以及非心腦血管性死亡、腎衰、心絞痛和短暫性腦缺血,患者百分數(shù)%,P=0.62,12.1,12.5,硝苯地平控釋片 利尿劑聯(lián)合用藥,NORDIL(the Nordic Diltiazem Stud

4、y),地爾硫卓、利尿劑和B-阻滯劑組均可顯著降低血壓(分別降低20.3/18.7mmHg，23.3/18.7 mmHg，收縮壓差異P<0.001)主要終點在 地爾硫卓、利尿劑和B-阻滯劑組無差異,每千病人年事件數(shù),RR=1.00 ( 95%CI 0.87-1.15 ), P=0.97,地爾硫卓D＋B,NICS-EH,National Intervention Cooperation Study in Elderly Hyp

5、ertensives,老年人高血壓的長期治療研究,裁木 筑石井 當(dāng)男日和田邦男橋山幸志郎佐久間 昭,荻原俊男飯村 攻小澤利男柳沼淑人NICE-EH 共同研究,桑島 巍竹田亮祜藤島正敏木野 康,阿部圭志增山善明竹卜 彰倉持節(jié)人,猿田 亨男榍山 梧朗島田 和幸海老原昭人,因心腦血管合并癥出現(xiàn)終止兩組累積進行率,累 積 進 行 率,時 間（日）,PATE-H Study,1748例日本

6、老年高血壓患者前瞻性開放臨床試驗比較delapril與manidipine單藥治療，平均隨訪28.4月一級終點:CVD發(fā)生率和死亡率,Practitioner’s Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension,PATE-H 一級終點事件(每1000病人年),Am J Hypertens 2000:13:461,老年人

7、高血壓臨床試驗終點事件數(shù)比較(/1000病人年),試驗安慰劑利尿劑或b-阻滯劑鈣拮抗劑轉(zhuǎn)換酶抑制劑EWPHE114.874.2SHEP68.349.3STOP-H55.533.5MRC II25.221.0Syst-Eur33.923.3Syst-China33.321.4PATH-H19.722.5,,,,(一) CVD事件,WHO/ISHBlood Pressure Lo

8、weringTrialists’ Collaboration(BPLT臨床試驗協(xié)作研究),BPLT協(xié)作研究的背景,在臨床試驗中肯定不同類型降壓藥對終點事件影響的差別需要1000個以上的事件數(shù)預(yù)先確定方案和入選試驗的匯萃分析能避免選擇和主觀偏差個例資料的匯萃分析比整組資料能提供更豐富的信息,BPLT協(xié)作研究入選臨床試驗標(biāo)準,隨機化分組每組病例隨訪>1000病人年1995年7月前尚未發(fā)表試驗的主要結(jié)果,入選的臨床試驗(一)

9、,簡稱病例數(shù) 對象計劃隨訪(年)完成AASK1200HBP+Renal (disease)52001ABCD950Diabetes51998ALLHAT40000HBP+CVD (risk)62002ANBP26000HBP 52002ASCOT18000HBP+CVD(risk)52003BENEDICT2400Diabetes32001

10、CAPPP10800HBP 51998CONVINCE15000HBP+CVD (risk)52001CSGTEI1650Diabetes+proteinuria 32000DIAB-HYCAR4000Diabetes+proteinuria 31999,,,入選的臨床試驗(二),簡稱病例數(shù)對象計劃隨訪(年)完成ELSA2251HBP 42000HDS1148HBP+

11、Diabetes 8.21998HOPE9541CVD (risk)4.72000HOT19196HBP 3.51997HYVET2100HBP 52001INSIGHT6592HBP+CVD (risk) 31999LIFE9194HBP+LVH 42001NICE-EH1000HBP 51997NORDIL11000HBP 52002

12、PART2617Atherosclerosis 41998PHYLLIS450CIT 32000,入選的臨床試驗(三),簡稱病例數(shù)對象計劃隨訪(年)完成PREVENT285ACHD51997PROGRESS6000 Stroke or TIA52000QUIET1750ACHD31996RENAAL1500Diabetes42002SCOPE4000HBP2.5

13、2003SHELL4800 HBP3.51999STOP-26628HBP41998SYST-EUR4695ISH1.61997VHAS1414HBP21996,BPLT協(xié)作研究一級終點,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

14、 provide good power 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 lik

15、ely to be suboptimal, so the principal focus of analyses at that time will be the combined outcome of total cardiovascular events.,J Hypertens 1998;16:127-137,BPLT協(xié)作研究第一輪分析入選的臨床試驗,降壓藥與安慰劑比較HOPE，PART2，QUIET，SCAT，PREVEN

16、T，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,相對危險計算,BPLT協(xié)作研究第一輪分析結(jié)果(一),ACEIs CCBs 利尿劑或b阻滯劑總死亡率0.84(0.76-0.94)0.87(0.70-1.09)0.87CVD死亡率0.74(0.64-0.85)0

17、.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),,,,與安慰劑作比較(RR),ACEI PlaceboRelative ri

18、sk(95% 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(0.7

19、3-0.86)(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)Overall307/6060416/60640.74(

20、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(

21、0.76-0.94)(p homog=0.74),Comparisons of ACE-inhibitor-based therapy with placebo,Number of events/total patients,,Relative riskFavorsFavorsACE-Iplacebo,BPLT: Lancet 2000; 355:1955,,,,,,,,,,,,0.51.02.0,,,,,,,,

22、,,,,,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 homog

23、=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-EU

24、R135/2398147/22970.88(0.70-1.10)Overall141/2815155/27050.87(0.70-1.09)(p homog=0.74),Number of events/total patients,,Comparisons of calcium-antagonist-based therapy with placebo,BPLT: Lancet 2000; 355:1955,,0.5

25、1.02.0,Relative riskFavorsFavorscaciumplaceboantagonists,,,,,,,,,,,,,,BPLT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)Stroke0.80(0.65-0.98)CHD0.81(0

26、.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

27、(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)HOT96/6262177/125281.09(0.85-1.39)UKPDS-HDS80/75858/3900.71(0.52-0.97)Overall182/7257

28、246/131510.90(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 ho

29、mog=0.02),Number of events/total patients,,Comparisons of more intersive blood pressure lowering strategieswith less intensive strategies,BPLT: Lancet 2000; 355:1955,,0.51.02.0,Relative riskFavorsFavorsmorele

30、ssintensiveintensive,,,,,,,,,,,,,,,,,,,,ACEIsCCBs 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)1.03(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

31、(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)

32、,,,,,,,ACE-IDiuretio 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

33、=0.12)CAPPP406/5492376/54931.08(0.94-1.24)Overall1018/80971004/80641.00(0.93-1.08)(p homog=0.12)Cardiovascular deathSTOP-2226/2205221/22131.03(0.86-1.22)UKPDS-HDS48/40032/3581.34(0.88-2.05)Subtotal274

34、/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-HDS75/40059/35

35、81.14(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),Number of events/total patients,,,0.51.02.0,

36、BPLT: Lancet 2000; 355:1955,,,,,,,,,,,,,,,,,,,,,,,,,ACE-1 CaiciumRelative riskantagonists(95% CI)Major cardiovascular eventsABCD28/23547/2350.60(0.39-0.92)STOP-2531/2205562/21960.94(0.85-1.04)Overall559

37、/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 mortalltyABCD

38、14/23518/2350.78(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),Number of events/total patients,,Comparisons of ACE-inhibitor-based therapywith calcium-an

39、tagonist-based therapy,BPLT: Lancet 2000; 355:1955,,0.51.02.0,Relative riskFavorsFavorsACE-1calciumantagonists,,,,,,,,,,,,,,BPLT協(xié)作研究第一輪分析的結(jié)論,證實ACEIs和長效CCBs降壓治療能顯著減少CVD事件發(fā)生與CVD死亡率積極降壓治療對減少CVD事件發(fā)生能增加益處相對于

40、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,入選的臨床試驗數(shù)、病例數(shù)和事件數(shù)尚未達到作出肯定結(jié)論的條件，尤其在評價不同類型降壓藥對終點事件影響的差別時不同臨床試驗的樣本量相差很大，其中HOPE、SYST-EUR、HOT、STOP-2等試驗的結(jié)果起了決定性影響，而這些臨床試驗的對象和設(shè)計是特定的大部分入選的臨床試驗在治療過程中有較高的失隨訪率(>30%)，可能對意向治療

41、分析(ITT)的結(jié)果造成偏差,Projected Numbers of Subjects 2000 Based on Current Collaborating Studies,The role of blood pressure itself becomes predominant athigh blood pressure levels but is less important whenpressure is lower

42、and non-pressure-dependentmechanisms become of greater importance. The curvesare hypothetical.,降壓治療試驗終點事件比較(/1000病人年),匯萃分析 HOT 1990年 1994年腦卒中 4.2 3.2

43、 4.4心肌梗死 3.0 7.25 7.8CVD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

44、擇的主要因素,社會經(jīng)濟狀況　具體患者的心腦血管病危險因素狀況　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　臨床試驗獲得的證據(jù)強度,HOT Study -- 需要多少藥物控制血壓,Hansson et al. Lancet 1998; 351:1756,,,2個及以上藥物(69%),1個藥物(31%),,,,,,Combination therapy needed to ac

45、hievetarget 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

46、et al 1998,UKPDS 需要多少藥物控制血壓,UKPDS 38. BMJ 1998; 317:703-713,,1個藥物(29%),,,,,2 個藥物(44%),? 3個以上(27%),0 或 1 (69%),2 個藥物(23%),Less tight control,Tight control,? 3 個以上(8%),Control of Hypertension% Patients With BP Contr

47、olled,,,,,,,,,,,,,27%,22%,20.5%,20%,19%,USA12,Canada14,Finland16,Spain16,Australia16,<140/90 mm Hg,<160/95 mm Hg,,,,,,,,,,,,,,,,,6%,24%,22.5%,17.5%,9%,England13,France15,Germany16,Scotland16,India16,>65 yr only,

48、12. 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;16:747,14.Joffres et al. Am J Hypertens 1

49、997;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 b

50、elow 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). Excluded are those

51、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 t

52、reated 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 Control of Hyperten

53、sion 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）,,,,,,,,,,,,,,,,,,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,,Aus

54、t,,SHEP,,EWPHE,,,Coope,,STOP,相對益處(% 降低卒中),絕對益處(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Syst-Eur13.78.0Syst-China20.82.4,腦卒中/心肌梗死發(fā)病率比值,STONE8.0Syst-China8.7NICS-EH4.0SHEP1.2MRC II0

55、.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 心血管危險因素研究血壓水平以外的各項因素對CVD發(fā)生率的影響

56、,Risk factor CV/1000 pt.yRRCl(95%)YesNoGender(M vs F)12.07.21.62(1.42~1.94)Age(≥65 vs 65 yrs)15.07.32.06(1.77~2.39)Smoking 14.08.91.57(1.31~1.88)S-Cholesterol(>6.8 vs ≤6.8 mmol/l) 1

57、1.69.01.29(1.09~1.53) S-Creatinine(>1.3 vs ≤1.3 mg/dl) 21.88.72.50(2.03~3.07) Diabetes 18.39.02.03(1.65~2.51) Ischemic Heart Disease 18.48.12.27(1.93~2.68),,,,,結(jié)論和思考,抗高血壓臨床試驗已經(jīng)提供了降壓治療有益以及如何獲得較大益處的