基于临床试验高血压治疗策略.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,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,Trials,Year,Contributions,VA Trial,The VA Cooperative Study on Antihypertension Drugs,1967,Severe HT should be treated,HDFP,The HT Detection and Follow-up Program(Australia),1976,Large-scale CT could be,conducted well&successfully in,community,ANBPS,Australian National BP Study,1979,A 4-month observation period is,advisable before instituting drug,treatment,MRC trial,The MRC Trial of Treatment in Mild HT(British),1977,Absolute benefits were small in,mild HT,treat 850 pts save 1,stroke,Mild HT,a weak claim for,status as an entity,Trials,Year,Contributions,BHAT,-blocker Heart Attack Trial,1981,CHD could be reduced in POST-MI,pts.by,-blocker,EWPHE,The European working Party on High BP in the Elderly,1984,Elderly HT pts.would benefit from anti HT treatment,MRC ELDERLY TRIAL,Medical Research Council Trial of Treatment of HT in Older Adults,1987,demonstrated a significant reduction in stroke,cardiac and all CVD events,STOP-HT,The Swedish Trial in Old Pats.with HT,1991,Drug treatment in HT pts.70-84 reduce CVD morbidity&mortality&total mortality,Trials,Year,Contributions,SHEP,Systolic HT in the Elderly Reduced Total Stroke and all CHD,1991,Systolic HT in the elderly,ISH should be treated in older pts.,VA study on Monotherapy,1990,HCHZ greatly enhanced the efficacy of non-diuretic drugs,HCTZ 12.5mg,CDN,Captopril in Type 1 Diabetic Nephropathy,1992,Captopril,can reduce progression of,renal disease,improved survival,Doubling of Serum Cr.Endpoint,Syst.-China,Chnese Systolic HT in the Elderly Trial,1992,Total mortality,CVD mortality&Stroke mortality reduced by CCB based treatment,Trials,Year,Contributions,TOMHS Study,The Treatment of Mild HT Study,1993,Combined lifestyle/drug intervention in stage I HT is beneficial,PATs,Post Stroke Anti HT Treatment Study,1993,BP reduction in post stroke pts.is beneficial,even in normotensive,Syst.-Eur.,Syst.-Eur.Multicentre Trial,1997,New antihypertensive drugs,Prognosis of ISH,DM&dementia,ABP is a significant predictor of,outcome,HOT,HT Optimal Treatment Trial,1997,BP to goal is possible,Comb.therapy was necessary in 70%,pts.,Goal tolerability of anti HT,therapy,No,risk in“normalizing”BP,Intensive BP lowering in DM HT pts.,(130/80),Benefits of,antiplatelet,agents,Trials,Year,Contributions,STOP-HT-2,Swedish Trial in Old Pts.With HT,1998,Older&newer agents are effective in treating elderly HT pts.,PROGRESS,Perindopril Protection Against Recurrent Stroke Study,2000,BP reduction in post stroke pts.treated by Perindopril based treatment reduced stroke recurrence,even in normotensive,CONVINCE,Controlled Onset Verapamil Investigation for CVD Endpoints,2001,Large simple trials of treatment of,a chronic disease,Clinical practice,Technological progress,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,(%),0,10,20,30,40,50,0,10,20,30,40,50,(%),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 Overviewsof Randomized Trial,Trials,Patients,CV Events,All-together,29,162,341,17,348,ACEI or CA vs Placebo,9,25,711,3548,More or less intensive,5,21,982,1191,ARB vs Control,4,16,791,2478,ACEI,CA vs D,BB,16,101,228,10,131,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,ACEIvs 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,ACEIvs 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,ACEIvs 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,ACEIvs 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-BasedRegimens 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,-,-,5.61.9,-,-,-,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,China Urban,China Rural,USA,UK,Japan,0,200,400,600,800,China Urban,China Rural,Japan,UK,USA,CHD,Stroke,Other CVD,Other,Mortality,1/100000,Female,35-74,WHO,statistics,Mortality in China,Japan,UK,USA,Past Large-scale Clinical Studies on Asian People,Sample size,FU,yrs.,BP,End Point,Syst.-China,2,394,3,9/4,Total/CVD/Stroke Mortality,STONE,1,632,3,Events,59%,PATs,5,665,2,5/3,Stroke recurrence,29%,PROGRESS,1,520,+815,4.5,9/4,Prevent 1%stroke/year,Asian benefited more 2%/yr.,ICH benefit more2.5%/yr.,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,73,136,103,201,36,16,35,15,139,174,171,276,139,171,118,133,0,100,200,300,400,500,Stroke,CHD,Cardiovas,Vascular,Others,Fatal events,Non-fatal events,36%3%34%22%15%,(p0.001)(p=0.89)(p0.001)(p=0.03)(p=0.19),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(,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 an important lesson about the design,conduct,and analysis of future trials in hypertension,VALUE shows the importance of analysisof data at time-specific intervals over the course of a trial,VALUE:Implications,Julius 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,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!,