基于臨床試驗高血壓治療策略

1、Hypertension Treatment Strategy Based on Clinical Trials Liu Lisheng,Is antihypertensive treatment beneficial? Trials of active treatment vs. placebo (or more vs. less)When should drug treatment start?(BP lev

2、el? Mild hypertension? Risk stratifications?)Whom should be treated? (Severe, mild, ISH)To what extent?Is BP lowering by different antihypertensive agents equally beneficial?Necessity of Conducting Large-s

3、cale Clinical Studies using Asian Subjects,Is antihypertensive treatment beneficial? Trials of active treatment vs. placebo (or more vs. less)When should drug treatment start?(BP level? Mild hypertension? R

4、isk stratifications?)Whom should be treated? (Severe, mild, ISH)To what extent?Is BP lowering by different antihypertensive agents equally beneficial?Necessity of Conducting Large-scale Clinical Studies using As

5、ian Subjects,Isolated systolic hypertension,(%),,,,,,,,,,,,,(%),Stroke,CHD,Allcause,CV,NonCV,Fatal and non-fatal events,Mortality,,,,Systolic-diastolic hypertension,Stroke,CHD,Allcause,CV,NonCV,Fatal and non-fatal

6、events,Mortality,,,,Event Reduction in Patients on Active Antihypertensive Treatment versus Placebo or No Treatment,ESH-ESC Hypertension Guidelines. J Hypertens. 2003.,<0.01,<0.01,<0.001,NS,<0.001,<0.001,0

7、.02,0.01,NS,<0.001,Blood Pressure Lowering Treatment Trialists’ Collaboration Effects of Different Blood-Pressure-Lowering Regimens on Major Cardiovascular Events:,BPLT Trialists’ Collaboration. Lancet. 2003;362:1527–

8、35.,Results of Prospectively?Designed Overviewsof Randomized Trial,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Major Cardiovascular Events,BPLT Trialists’ Collaboration. Lancet. 2003;362:1527–35.,,Pla

9、cebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CA,Trials534695,Relative risk0.78 (0.73?0.83)0.82 (0.71?0.95)

10、0.85 (0.76?0.95)1.02 (0.98?1.07)1.04 (1.00?1.09)0.97 (0.92?1.03),,,,,0.5,1.0,2.0,Favours2nd listed,Favours1st listed,Relative risk,,,,,,,BP difference?5 / ?2?8 / ?4?4 / ?3+2 / 0+1 / 0+1 /+1,Meta-Analysi

11、s of Antihypertensive Treatment Trials: Effects on Stroke,BPLT Trialists’ Collaboration. Lancet. 2003;362:1527–35.,,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen s

12、tudiesACEI vs D/BBCA vs D/BBACEIvs CA,Trials544595,BP difference?5 / ?2?8 / ?4?4 / ?3+2 / 0+1 / 0+1 /+1,Relative risk0.72 (0.64?0.81)0.62 (0.47?0.82)0.77 (0.63?0.95)1.09 (1.00?1.18)0

13、.93 (0.86?1.00)1.12 (1.01?1.25),,,,0.5,1.0,2.0,Favours2nd listed,Favours1st listed,Relative risk,,,,,,,,Meta-Analysis of Antihypertensive Treatment Trials: Effects on CHD Events,BPLT Trialists’ Collaboration. Lancet.

14、2003;362:1527–35.,,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CA,Trials544595,Relative risk0.80 (0.73?0

15、.88)0.78 (0.62?0.99)0.95 (0.81?1.11)0.98 (0.91?1.05)1.01 (0.94?1.08)0.96 (0.88?1.04),,,,0.5,1.0,2.0,Favours2nd listed,Favours1st listed,Relative risk,,,,,,,,BP difference?5 / ?2?8 / ?4?4 / ?3+2 / 0+1 /

16、 0+1 /+1,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Heart Failure,BPLT Trialists’ Collaboration. Lancet. 2003;362:1527–35.,,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs les

17、sActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CA,Trials534374,Relative risk0.82 (0.69?0.98)1.21 (0.93?1.58)0.84 (0.59?1.18)1.07 (0.96?1.19)1.33 (1.21?1.47)0.82 (0.73?0.92),,,

18、,0.5,1.0,2.0,Favours2nd listed,Favours1st listed,Relative risk,,,,,,,,BP difference?5 / ?2?8 / ?4?4 / ?3+2 / 0+1 / 0+1 /+1,Comparisons of ARB-BasedRegimens With Control Regimens,BPLT Trialists’ Collaboratio

19、n. Lancet. 2003;362:1527–35.,,,,,0.5,1.0,2.0,FavoursControl,FavoursARB,Relative risk,,,,,,,,StrokeCHDHeartfailureMajor CVeventsCV deathTotalmortality,Trials443444,Relative risk(95% CI)0.7

20、9 (0.69?0.90)0.96 (0.85?1.09)0.84 (0.72?0.97)0.90 (0.83?0.96)0.96 (0.85?1.08)0.94 (0.86?1.02),396/8412 435/8412 302/59351135/8412 491/8412 887/8412,500/8379 450/8379 359/59191268/8

21、379 511/8379 943/8379,Diff. in BP(mean, mmHg)?2 / ?1?2 / ?1?2 / ?1?2 / ?1?2 / ?1?2 / ?1,P0.460.430.260.780.340.59,Events / Participants,Trials Comparing Different Antihypertensive Re

22、gimens: New Onset Diabetes,Zanchetti, Ruilope. J Hypertens. 2002;20:2099–110.,TrialSHEPHOPENORDILSTOP-2INSIGHTNICS-EHCAPPPSTOP-2STOP-2LIFESCOPEALLHATALLHATINVEST,ComparisonD vs PACE vs PCA vs D/?BCA v

23、s D/?BCA vs DCA vs DACEI vs D/?BACEI vs D/?BACEI vs CAAIIA vs ?BAIIA vs usualD vs CAD vs ACEICA vs ?B,Years3 4.5 4.55 3.55 6.155 4.8 3.744 2.7,1 8.6 3.6-- 4.30---6 4

24、.311.611.6 6.9,PNS< 0.001NSNS< 0.05NS 0.039NSNS< 0.001 0.09 0.04< 0.001,Treatment,,,27.55.4--5.61.9---85.39.89.17.9,--9.49.9---9.69.613.0,2--10.810.0---

25、10.0 9.917.4,RR (95% CI)-0.66 (0.51?0.85)0.87 (0.73?1.04)0.97 (0.73?1.29)--0.86 (0.74?0.99)0.96 (0.72?1.27)0.98 (0.74?1.31)0.75 (0.63?0.88)---0.87 (0.78?0.97),% patient,,n/1000 pt yr,,New-onset diabetes

26、,,1,Limitations of Event-Based Trials,Trials are of relatively short duration (3-5 years) and cover a small proportion of the life expectancy of middle-aged uncomplicated hypertensives.Most trials have recruited complic

27、ated hypertensives only. Are the results of these trials applicable to younger uncomplicated hypertensives?Intermediate endpoints (subclinical target organ damage) may provide a better indication of long-term difference

28、s between the effects of antihypertensive agents.,Zanchetti 2004,Event-Based Versus TOD-Based Trials,When trials include hypertensives with advanced organ damage and at high risk of early CV events, intensive BP lowering

29、 can effectively prevent a number of events, but it is likely to be unable to influence organ damage, and the ancillary properties of different antihypertensive agents may remain masked.In less advanced disease and when

30、 the risk of events is lower and delayed, the different ability of different agents to influence organ damage progression may be translated into differences in long-term benefits.,Zanchetti 2004,Choice of Antihypertensiv

31、e Drugs,Differences in some effect or in some group of patients may existARA more effective than βB or usual therapy for stroke in LVH or elderlyDiuretics, alone or in combination, particularly effective for CHFACEI a

32、nd ARA more effective on diabetic and nondiabetic nephropathyARA more effective than βB in LVHCA more effective than D and βB on carotid atherosclerosisACEI more effective than D on carotid atherosclerosisDrugs are n

33、ot equal in terms of adverse disturbances,Confirmation of previous WHO-ISH guidelines: the main benefits of antihypertensive therapy are due to lowering BP per se,ESH-ESC Hypertension guidelines J Hypertens 2003,Trials C

34、omparing Different Active Antihypertensive Agents is Difficult,Because: Smaller relative benefits to be expected. Hence, large sample size, high risk pts. need to be randomized.,Is antihypertensive treatment be

35、neficial? Trials of active treatment vs. placebo (or more vs. less)When should drug treatment start?(BP level? Mild hypertension? Risk stratifications?)Whom should be treated? (Severe, mild, ISH)To w

36、hat extent?Is BP lowering by different antihypertensive agents equally beneficial?Necessity of Conducting Large-scale Clinical Studies using Asian Subjects,Morbidity & Mortality of CVD in Asian Countries,,,,Mortali

37、ty in China, Japan, UK, USA,,,WHO statistics,Other,Other,Stroke,,,,,,,,,,,,CHD,,,,,CVD,,,Mortality 1/100000 Male 35-74,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,,500,,1000,,1500,,,,,,,,

38、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,200,400,600,800,,,,,,,,China Urban,China Rural,Japan,UK,US

39、A,Mortality 1/100000 Female 35-74,WHO statistics,Mortality in China, Japan, UK, USA,Past Large-scale Clinical Studies on Asian People,Syst. - China,Active treatment, stroke ? 38% (p=.01). All CVD end points ? 37% (p

40、=.004) and total mortality ? 39% (p=.003). 1,000 Chinese pt. for 5yr prevent 39 strokes 59 major CVD complications, or 55 death.The benefit was particularly evident in diabetic pts.,Effects of Antihypertensive Treatme

41、nt in 4 Clinical Trials in China,Note: 10,400 pts, av FU 3 yrs, av SBP? 9 mmHg, DBP ? 4 mmHg. Trials: PATS, Syst-China, STONE and CNIT. T = Treatment, C = Control,,Are ALLHAT & VALUE Applicable to Asian People?,ALL

42、HAT,Long acting CCBs are safeBP lowing is most importantCombination therapy is often necessaryAmlodipine is the first choice for preventing stroke,,VALUE: Main Results,Good BP control was achieved with both treatment

43、 regimens, but BP decrease in the amlodipine group was more pronounced, particularly early in the trialDespite BP differences, the primary composite cardiac endpoint in both groups was not different,Julius S et al. Lan

44、cet. June 2004;363.,,VALUE: Other Results,Incidence of stroke was lower, but not significantly, in the amlodipine groupIncidence of non-fatal MI was significantly lower in the amlodipine groupThere was a positive trend

45、 in favour of valsartan for less heart failure but this did not reach significanceThere was a highly significant lower rate of new-onset diabetes in the valsartan group,Julius S et al. Lancet. June 2004;363.,The observe

46、d difference in stroke rates appears to be strongly related to differences in achieved BPsThe benefits of valsartan in heart failure prevention emerged later in the study when BP differences were smaller, indicating tha

47、t there is a potential beneficial effect of valsartan beyond BP control,,VALUE: Interpretations,Julius S et al. Lancet. June 2004;363.,,VALUE: Interpretations,VALUE is the first trial to show a lower rate of new-onset di

48、abetes when an ARB (valsartan) was compared to a CCB (amlodipine) Long-term implications and mechanisms of this important finding deserve further investigation,Julius S et al. Lancet. June 2004;363.,Our results provide

49、an important lesson about the design, conduct, and analysis of future trials in hypertensionVALUE shows the importance of analysisof data at time-specific intervals over the course of a trial,VALUE: Implications,Julius

50、 S et al. Lancet. June 2004;363.,,Prompt blood pressure control in hypertensive patients at high cardiovascular risk is very important The between-group differences in heart failure and diabetes suggest that valsartan m

51、ay offer benefits beyond BP control,VALUE: Conclusions,Julius S et al. Lancet. June 2004;363.,What do We Expect for Future Large-scale Clinical Studies,Compare different combinations in stead of single drugEasy to be co