基于临床试验高血压治疗策略课件

1、基于临床试验高血压治疗策略基于临床试验高血压治疗策略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 anti

2、hypertensive agents equally beneficial?Necessity of Conducting Large-scale Clinical Studies using Asian SubjectsIs antihypertensive treatment 基于临床试验高血压治疗策略课件基于临床试验高血压治疗策略课件TrialsYear Contributions SHEPSystolic HT in the Elderly Reduced Total Stroke and all CHD 1991Systolic HT in the elderly, ISH sho

3、uld be treated in older pts. VA study on Monotherapy 1990HCHZ greatly enhanced the efficacy of non-diuretic drugs, HCTZ 12.5mgCDN Captopril in Type 1 Diabetic Nephropathy 1992 Captopril can reduce progression of renal disease improved survival Doubling of Serum Cr. EndpointSyst.-ChinaChnese Systolic

4、 HT in the Elderly Trial 1992Total mortality, CVD mortality & Stroke mortality reduced by CCB based treatmentTrialsYear Contributions SHEP TrialsYear ContributionsTOMHS StudyThe Treatment of Mild HT Study1993Combined lifestyle/drug intervention in stage I HT is beneficialPATs Post Stroke Anti HT Tre

5、atment Study 1993 BP reduction in post stroke pts. is beneficial, even in normotensive Syst.-Eur. Syst.-Eur. Multicentre Trial1997 New antihypertensive drugs Prognosis of ISH, DM & dementia ABP is a significant predictor of outcomeHOT HT Optimal Treatment Trial1997 BP to goal is possible Comb. thera

6、py 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 agentsTrialsYear ContributionsTOMHS TrialsYear ContributionsSTOP-HT-2Swedish Trial in Old Pts. With HT1998Older & newer agents are effec

7、tive in treating elderly HT pts.PROGRESSPerindopril Protection Against Recurrent Stroke Study2000BP 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 simp

8、le trials of treatment of a chronic disease Clinical practice Technological progressTrialsYear ContributionsSTOP-HTrialsYear ContributionsLIFELosartan Intervention for endpoint Reduction in HT2001Losartan vs Atendol, primary composite endpoints 25% first stroke 25% less new-onset DMALLHAT Antihypert

9、ensive therapy and lipid-lowering heart attack prevention trial2002Compare different antihypertensive drugs ANBP2Australian National BP Study 22002 comparison of ACEI & diureticsTrialsYear ContributionsLIFE20TrialsYear ContributionsVALUE Diovan Antihypertensive long-term Use Evaluation2004 Prompt BP

10、 control in high risk hypertensive pts. is important VAS can reduce new onset DMASCOT2005CCB + ACEI B-blocker + DiureticsFEVERChinese Felodipine Event Reduction Trial2005 More or less antihypertensive treatment on stroke Reach target is important TrialsYear ContributionsVALUE Is antihypertensive tre

11、atment 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

12、of Conducting Large-scale Clinical Studies using Asian SubjectsIs antihypertensive treatment Isolated systolic hypertension(%)0102030405001020304050(%)StrokeCHDAllcauseCVNonCVFatal and non-fatal eventsMortalitySystolic-diastolic hypertensionStrokeCHDAllcauseCVNonCVFatal and non-fatal eventsMortality

13、Event Reduction in Patients on Active Antihypertensive Treatment versus Placebo or No TreatmentESH-ESC Hypertension Guidelines. J Hypertens. 2003.0.010.010.001NS0.0010.0010.020.01NS0.001Isolated systolic hypertensionBlood Pressure Lowering Treatment Trialists Collaboration Effects of Different Blood

14、-Pressure-Lowering Regimens on Major Cardiovascular Events:BPLT Trialists Collaboration. Lancet. 2003;362:152735.Results of ProspectivelyDesigned Overviewsof Randomized TrialTrialsPatientsCV EventsAll-together29162,34117,348ACEI or CA vs Placebo925,7113548More or less intensive521,9821191ARB vs Cont

15、rol416,7912478ACEI, CA vs D, BB16101,22810,131Blood Pressure Lowering TreatmMeta-Analysis of Antihypertensive Treatment Trials: Effects on Major Cardiovascular EventsBPLT Trialists Collaboration. Lancet. 2003;362:152735.Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs acti

16、ve regimen studiesACEI vs D/BBCA vs D/BBACEIvs CATrials534695Relative 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)0.51.02.0Favours2nd listedFavours1st listedRelative riskBP difference5 / 28 / 44 / 3+2 / 0+1 / 0+1 /+1Meta-Analysis of AntihypertensMeta

17、-Analysis of Antihypertensive Treatment Trials: Effects on StrokeBPLT Trialists Collaboration. Lancet. 2003;362:152735.Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CATrials544595BP difference5 / 28 / 44 / 3+2 / 0+1 / 0

18、+1 /+1Relative risk0.72 (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)0.51.02.0Favours2nd listedFavours1st listedRelative riskMeta-Analysis of AntihypertensMeta-Analysis of Antihypertensive Treatment Trials: Effects on CHD EventsBPLT Trialists Collaboration. La

19、ncet. 2003;362:152735.Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CATrials544595Relative 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)0.51.02.0Favours2nd listedFavours1

20、st listedRelative riskBP difference5 / 28 / 44 / 3+2 / 0+1 / 0+1 /+1Meta-Analysis of AntihypertensMeta-Analysis of Antihypertensive Treatment Trials: Effects on Heart FailureBPLT Trialists Collaboration. Lancet. 2003;362:152735.Placebo-controlled studiesACEI vs placeboCA vs placeboMore vs lessActive

21、 vs active regimen studiesACEI vs D/BBCA vs D/BBACEIvs CATrials534374Relative 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)0.51.02.0Favours2nd listedFavours1st listedRelative riskBP difference5 / 28 / 44 / 3+2 / 0+1 / 0+1 /+1Meta-Analysis of Antihyper

22、tensComparisons of ARB-BasedRegimens With Control RegimensBPLT Trialists Collaboration. Lancet. 2003;362:15272.0FavoursControlFavoursARBRelative riskStrokeCHDHeartfailureMajor CVeventsCV deathTotalmortalityTrials443444Relative risk(95% CI)0.79 (0.690.90)0.96 (0.851.09)0.84 (0.720.97)0.90 (0

23、.830.96)0.96 (0.851.08)0.94 (0.861.02) 396/8412 435/8412 302/59351135/8412 491/8412 887/8412 500/8379 450/8379 359/59191268/8379 511/8379 943/8379Diff. in BP(mean, mmHg)2 / 12 / 12 / 12 / 12 / 12 / 1P0.460.430.260.780.340.59Events / ParticipantsComparisons of ARB-BasedRegimTrials Comparing Different

24、 Antihypertensive Regimens: New Onset DiabetesZanchetti, Ruilope. J Hypertens. 2002;20:2099110.TrialSHEPHOPENORDILSTOP-2INSIGHTNICS-EHCAPPPSTOP-2STOP-2LIFESCOPEALLHATALLHATINVESTComparisonD vs PACE vs PCA vs D/BCA vs D/BCA vs DCA vs DACEI vs D/BACEI vs D/BACEI vs CAAIIA vs BAIIA vs usualD vs CAD vs

25、ACEICA vs BYears3 4.5 4.55 3.55 6.155 4.8 3.744 2.71 8.6 3.6- 4.30-6 4.311.611.6 6.9PNS 0.001NSNS 0.05NS 0.039NSNS 0.001 0.09 0.04 0.001Treatment27.55.4-5.61.9-7.9-9.49.9-9.69.613.02-10.810.0-10.0 9.917.4RR (95% CI)-0.66 (0.510.85)0.87 (0.731.04)0.97 (0.731.29)-0.86 (0.740.99)0.96 (0.721.2

26、7)0.98 (0.741.31)0.75 (0.630.88)-0.87 (0.780.97)% patientn/1000 pt yrNew-onset diabetes1Trials Comparing Different AntLimitations of Event-Based TrialsTrials are of relatively short duration (3-5 years) and cover a small proportion of the life expectancy of middle-aged uncomplicated hypertensives.Mo

27、st 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.

28、Zanchetti 2004Limitations of Event-Based TriEvent-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,

29、 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.Zan

30、chetti 2004Event-Based Versus TOD-Based TChoice of Antihypertensive DrugsDifferences in some effect or in some group of patients may existARA more effective than B or usual therapy for stroke in LVH or elderlyDiuretics, alone or in combination, particularly effective for CHFACEI and ARA more effecti

31、ve on diabetic and nondiabetic nephropathyARA more effective than B in LVHCA more effective than D and B on carotid atherosclerosisACEI more effective than D on carotid atherosclerosisDrugs are not equal in terms of adverse disturbancesConfirmation of previous WHO-ISH guidelines: the main benefits o

32、f antihypertensive therapy are due to lowering BP per seESH-ESC Hypertension guidelines J Hypertens 2003Choice of Antihypertensive DruTrials Comparing Different Active Antihypertensive Agents is DifficultBecause: Smaller relative benefits to be expected. Hence, large sample size, high risk pts. need

33、 to be randomized.Trials Comparing Different ActIs 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 lowe

34、ring by different antihypertensive agents equally beneficial?Necessity of Conducting Large-scale Clinical Studies using Asian SubjectsIs antihypertensive treatment Morbidity & Mortality of CVD in Asian CountriesMorbidity & Mortality of CVD iMortality in China, Japan, UK, USAWHO statisticsOtherOtherS

35、trokeCHDCVDMortality 1/100000 Male 35-74050010001500China UrbanChina RuralUSAUKJapanMortality in China, Japan, UK, 0200400600800China UrbanChina RuralJapanUKUSACHDStrokeOther CVDOtherMortality 1/100000 Female 35-74WHO statisticsMortality in China, Japan, UK, USA Past Large-scale Clinical Studies on

36、Asian PeopleSample sizeFUyrs.BP End PointSyst.-China2,39439/4Total/CVD/Stroke MortalitySTONE1,6323Events 59% PATs5,66525/3Stroke recurrence 29% PROGRESS1,520+8154.59/4 Prevent 1% stroke/year Asian benefited more 2%/yr. ICH benefit more2.5%/yr.Past Large-scale Clinical StudSyst. - ChinaActive treatme

37、nt, 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. Syst. - ChinaActive treatment,Effects of Antihypertensive Treatment in

38、4 Clinical Trials in ChinaNote: 10,400 pts, av FU 3 yrs, av SBP 9 mmHg, DBP 4 mmHg. Trials: PATS, Syst-China, STONE and CNIT. T = Treatment, C = Control73136103201361635151391741712761391711181330100200300400500StrokeCHDCardiovasVascularOthersFatal eventsNon-fatal events 36% 3% 34% 22% 15% (p0.001)

39、(p=0.89) (p0.001) (p=0.03) (p=0.19)Effects of Antihypertensive TrAre ALLHAT & VALUE Applicable to Asian People?Are ALLHAT & VALUE Applicable ALLHATLong acting CCBs are safeBP lowing is most importantCombination therapy is often necessaryAmlodipine is the first choice for preventing strokeALLHATLong

40、acting CCBs are saVALUE: Main ResultsGood BP control was achieved with both treatment 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 differentJulius S et al. L

41、ancet. June 2004;363.VALUE: Main ResultsGood BP conVALUE: Other ResultsIncidence 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 in favour of valsartan for less heart failure but th

42、is did not reach significanceThere was a highly significant lower rate of new-onset diabetes in the valsartan groupJulius S et al. Lancet. June 2004;363.VALUE: Other ResultsIncidence The observed 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 that there is a potential bene