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 level? Mild hypertension? Risk stratifications?) Whom should be treated? (Severe, mild, ISH) T
2、o what extent? Is BP lowering by different antihypertensive agents equally beneficial? Necessity of Conducting Large-scale 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 le
3、vel? 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-scale Clinical Studies using Asian Subjects,Isolated systolic hypertension,(%),(%),Stroke,C
4、HD,All cause,CV,Non CV,Fatal and non-fatal events,Mortality,Systolic-diastolic hypertension,Stroke,CHD,All cause,CV,Non CV,Fatal and non-fatal events,Mortality,Event Reduction in Patients on Active Antihypertensive Treatment versus Placebo or No Treatment,ESH-ESC Hypertension Guidelines. J Hypertens
5、. 2003.,0.01,0.01,0.001,NS,0.001,0.001,0.02,0.01,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;362:152735.,Results of ProspectivelyDesigned Overviews
6、of Randomized Trial,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Major Cardiovascular Events,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEI vs CA,Tri
7、als5 3 46 9 5,Relative risk0.78 (0.730.83) 0.82 (0.710.95) 0.85 (0.760.95)1.02 (0.981.07) 1.04 (1.001.09) 0.97 (0.921.03),0.5,1.0,2.0,Favours 2nd listed,Favours 1st listed,Relative risk,BP difference5 / 2 8 / 4 4 / 3+2 / 0 +1 / 0 +1 /+1,Meta-Analysis of Antihypertensive Treatment Trials: Effects on
8、Stroke,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEI vs CA,Trials5 4 45 9 5,BP difference5 / 2 8 / 4 4 / 3+2 / 0 +1 / 0 +1 /+1,Relative risk0.72 (0.640.81) 0.62 (0.47
9、0.82) 0.77 (0.630.95)1.09 (1.001.18) 0.93 (0.861.00) 1.12 (1.011.25),0.5,1.0,2.0,Favours 2nd listed,Favours 1st listed,Relative risk,Meta-Analysis of Antihypertensive Treatment Trials: Effects on CHD Events,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studiesACEI vs plac
10、eboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEI vs CA,Trials5 4 45 9 5,Relative risk0.80 (0.730.88) 0.78 (0.620.99) 0.95 (0.811.11)0.98 (0.911.05) 1.01 (0.941.08) 0.96 (0.881.04),0.5,1.0,2.0,Favours 2nd listed,Favours 1st listed,Relative risk,BP difference5 / 2
11、 8 / 4 4 / 3+2 / 0 +1 / 0 +1 /+1,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Heart Failure,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEI vs CA,Tria
12、ls5 3 43 7 4,Relative risk0.82 (0.690.98) 1.21 (0.931.58) 0.84 (0.591.18)1.07 (0.961.19) 1.33 (1.211.47) 0.82 (0.730.92),0.5,1.0,2.0,Favours 2nd listed,Favours 1st listed,Relative risk,BP difference5 / 2 8 / 4 4 / 3+2 / 0 +1 / 0 +1 /+1,Comparisons of ARB-Based Regimens With Control Regimens,BPLT Tri
13、alists Collaboration. Lancet. 2003;362:152735.,0.5,1.0,2.0,Favours Control,Favours ARB,Relative risk,StrokeCHDHeart failureMajor CV eventsCV deathTotal mortality,Trials443444,Relative risk (95% CI)0.79 (0.690.90)0.96 (0.851.09)0.84 (0.720.97)0.90 (0.830.96)0.96 (0.851.08)0.94 (0.861.02),396/8412435/
14、8412302/59351135/8412491/8412887/8412,500/8379450/8379359/59191268/8379511/8379943/8379,Diff. in BP (mean, mmHg)2 / 12 / 12 / 12 / 12 / 12 / 1,P0.460.430.260.780.340.59,Events / Participants,Trials Comparing Different Antihypertensive Regimens: New Onset Diabetes,Zanchetti, Ruilope. J Hypertens. 200
15、2;20:2099110.,TrialSHEP HOPE NORDIL STOP-2 INSIGHT NICS-EH CAPPP STOP-2 STOP-2 LIFE SCOPE ALLHAT ALLHAT INVEST,ComparisonD vs P ACE vs P CA vs D/B CA vs D/B CA vs D CA vs D ACEI vs D/B ACEI vs D/B ACEI vs CA AIIA vs B AIIA vs usual D vs CA D vs ACEI CA vs B,Years34.54.5 53.5 56.1 5 54.83.7 4 42.7,18
16、.63.6 - -4.3 0 - - - 64.3 11.6 11.66.9,PNS 0.001 NS NS 0.05 NS0.039 NS NS 0.0010.090.04 0.001,Treatment,27.5 5.4 - - 5.6 1.9 - - - 8 5.3 9.8 9.1 7.9,- - 9.4 9.9 - - - 9.6 9.6 13.0,2- - 10.8 10.0 - - - 10.09.9 17.4,RR (95% CI)- 0.66 (0.510.85) 0.87 (0.731.04) 0.97 (0.731.29) - - 0.86 (0.740.99) 0.96
17、(0.721.27) 0.98 (0.741.31) 0.75 (0.630.88) - - - 0.87 (0.780.97),% patient,n/1000 pt yr,New-onset diabetes,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 tria
18、ls have recruited complicated 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 differences between the effects of antihypertensive agents.,Zanch
19、etti 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 can effectively prevent a number of events, but it is likely to be unable to influence organ damage, and the ancillary properties of d
20、ifferent antihypertensive agents may remain masked. In less advanced disease and when 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 Antihypert
21、ensive Drugs,Differences in some effect or in some group of patients may exist ARA more effective than B or usual therapy for stroke in LVH or elderly Diuretics, alone or in combination, particularly effective for CHF ACEI and ARA more effective on diabetic and nondiabetic nephropathy ARA more effec
22、tive than B in LVH CA more effective than D and B on carotid atherosclerosis ACEI more effective than D on carotid atherosclerosis Drugs are not equal in terms of adverse disturbances,Confirmation of previous WHO-ISH guidelines: the main benefits of antihypertensive therapy are due to lowering BP pe
23、r se,ESH-ESC Hypertension guidelines J Hypertens 2003,Trials Comparing 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 beneficial? Trials of active t
24、reatment 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 what extent? Is BP lowering by different antihypertensive agents equally beneficial? Necessity of Conducting Large-scale Clinic
25、al Studies using Asian Subjects,Morbidity & Mortality of CVD in Asian Countries,Mortality in China, Japan, UK, USA,WHO statistics,Other,Other,Stroke,CHD,CVD,Mortality 1/100000 Male 35-74,0,500,1000,1500,0,200,400,600,800,China Urban,China Rural,Japan,UK,USA,Mortality 1/100000 Female 35-74,WHO statis
26、tics,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=.004) and total mortality 39% (p=.003). 1,000 Chinese pt. for 5yr prevent 39 strokes 59 major CVD complications, or 55 death. The be
27、nefit was particularly evident in diabetic pts.,Effects of Antihypertensive Treatment 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?,ALLHAT,Lon
28、g acting CCBs are safe BP lowing is most important Combination therapy is often necessary Amlodipine is the first choice for preventing stroke,VALUE: Main Results,Good BP control was achieved with both treatment regimens, but BP decrease in the amlodipine group was more pronounced, particularly earl
29、y in the trialDespite BP differences, the primary composite cardiac endpoint in both groups was not different,Julius S et al. Lancet. June 2004;363.,VALUE: Other Results,Incidence of stroke was lower, but not significantly, in the amlodipine group Incidence of non-fatal MI was significantly lower in
30、 the amlodipine group There was a positive trend in favour of valsartan for less heart failure but this did not reach significance There was a highly significant lower rate of new-onset diabetes in the valsartan group,Julius S et al. Lancet. June 2004;363.,The observed difference in stroke rates app
31、ears to be strongly related to differences in achieved BPs The benefits of valsartan in heart failure prevention emerged later in the study when BP differences were smaller, indicating that there is a potential beneficial effect of valsartan beyond BP control,VALUE: Interpretations,Julius S et al. L
32、ancet. June 2004;363.,VALUE: Interpretations,VALUE is the first trial to show a lower rate of new-onset diabetes 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;
33、363.,Our results provide an important lesson about the design, conduct, and analysis of future trials in hypertension VALUE shows the importance of analysis of data at time-specific intervals over the course of a trial,VALUE: Implications,Julius S et al. Lancet. June 2004;363.,Prompt blood pressure
34、control in hypertensive patients at high cardiovascular risk is very important The between-group differences in heart failure and diabetes suggest that valsartan may 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 drug Easy to be conducted in daily practice Intermediate end-point include TOD markers, MA, PWV, 24hrABPM, LVH, should be monitored New onset DM is an important end point to be examined in future clinical trials,Thank You !,
