基于临床试验高血压治疗策略

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) To 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 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 Clinical Studies using Asian Subjects,Isolated systolic hypertension,(%),(%),Stroke,CHD,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. 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 of Randomized Trial,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Major Cardiovascular Events,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studies ACEI vs placebo CA vs placebo More vs less Active vs active regimen studies ACEI vs D/BB CA vs D/BB ACEI vs CA,Trials 5 3 4 6 9 5,Relative risk 0.78 (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 difference 5 / 2 8 / 4 4 / 3 +2 / 0 +1 / 0 +1 /+1,Meta-Analysis of Antihypertensive Treatment Trials: Effects on Stroke,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,Placebo-controlled studies ACEI vs placebo CA vs placebo More vs less Active vs active regimen studies ACEI vs D/BB CA vs D/BB ACEI vs CA,Trials 5 4 4 5 9 5,BP difference 5 / 2 8 / 4 4 / 3 +2 / 0 +1 / 0 +1 /+1,Relative risk 0.72 (0.640.81) 0.62 (0.470.82) 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 studies ACEI vs placebo CA vs placebo More vs less Active vs active regimen studies ACEI vs D/BB CA vs D/BB ACEI vs CA,Trials 5 4 4 5 9 5,Relative risk 0.80 (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 difference 5 / 2 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 studies ACEI vs placebo CA vs placebo More vs less Active vs active regimen studies ACEI vs D/BB CA vs D/BB ACEI vs CA,Trials 5 3 4 3 7 4,Relative risk 0.82 (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 difference 5 / 2 8 / 4 4 / 3 +2 / 0 +1 / 0 +1 /+1,Comparisons of ARB-Based Regimens With Control Regimens,BPLT Trialists Collaboration. Lancet. 2003;362:152735.,0.5,1.0,2.0,Favours Control,Favours ARB,Relative risk,Stroke CHD Heart failure Major CV events CV death Total mortality,Trials 4 4 3 4 4 4,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),396/8412 435/8412 302/5935 1135/8412 491/8412 887/8412,500/8379 450/8379 359/5919 1268/8379 511/8379 943/8379,Diff. in BP (mean, mmHg) 2 / 1 2 / 1 2 / 1 2 / 1 2 / 1 2 / 1,P 0.46 0.43 0.26 0.78 0.34 0.59,Events / Participants,Trials Comparing Different Antihypertensive Regimens: New Onset Diabetes,Zanchetti, Ruilope. J Hypertens. 2002;20:2099110.,Trial SHEP HOPE NORDIL STOP-2 INSIGHT NICS-EH CAPPP STOP-2 STOP-2 LIFE SCOPE ALLHAT ALLHAT INVEST,Comparison D 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,Years 3 4.5 4.5 5 3.5 5 6.1 5 5 4.8 3.7 4 4 2.7,1 8.6 3.6 - - 4.3 0 - - - 6 4.3 11.6 11.6 6.9,P NS 0.001 NS NS 0.05 NS 0.039 NS NS 0.001 0.09 0.04 0.001,Treatment,2 7.5 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 - - - 10.0 9.9 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 (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 trials 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.,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 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 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 Antihypertensive 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 effective 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 per 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 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 what 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,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 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=.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 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,Long 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 early in the trial Despite 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 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 appears 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. Lancet. June 2004;363.,VALUE: Interpretations,VALUE is the first trial to show a lower rate of new-onset diabetes when an ARB (val