1、 Hypertension Treatment Hypertension Treatment Strategy Based on Strategy Based on Clinical TrialsClinical Trials 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?)

2、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 SubjectsTrialsYear Contributions VA Trial The VA Cooperative Study on Antihypertension Drugs1967 Severe

3、 HT should be treatedHDFPThe HT Detection and Follow-up Program(Australia)1976 Large-scale CT could be conducted well & successfully in communityANBPSAustralian National BP Study1979 A 4-month observation period is advisable before instituting drug treatmentMRC trialThe MRC Trial of Treatment in

4、 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 entityTrialsYear Contributions BHAT- blocker Heart Attack Trial 1981 CHD could be reduced in POST-MI pts. by -blocker EWPHEThe European working Party on High BP in the El

5、derly 1984Elderly HT pts. would benefit from anti HT treatmentMRC ELDERLY TRIALMedical Research Council Trial of Treatment of HT in Older Adults1987demonstrated a significant reduction in stroke, cardiac and all CVD events STOP-HTThe Swedish Trial in Old Pats. with HT1991Drug treatment in HT pts. 70

6、-84 reduce CVD morbidity & mortality & total mortalityTrialsYear Contributions SHEPSystolic HT in the Elderly Reduced Total Stroke and all CHD 1991Systolic HT in the elderly, ISH should be treated in older pts. VA study on Monotherapy 1990HCHZ greatly enhanced the efficacy of non-diuretic dr

7、ugs, 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 HT in the Elderly Trial 1992Total mortality, CVD mortality & Stroke mortality reduced by CCB based treatm

8、entTrialsYear ContributionsTOMHS StudyThe Treatment of Mild HT Study1993Combined lifestyle/drug intervention in stage I HT is beneficialPATs Post Stroke Anti HT Treatment Study 1993 BP reduction in post stroke pts. is beneficial, even in normotensive Syst.-Eur. Syst.-Eur. Multicentre Trial1997 New a

9、ntihypertensive drugs Prognosis of ISH, DM & dementia ABP is a significant predictor of outcomeHOT HT Optimal Treatment Trial1997 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. (1

10、30/80) Benefits of antiplatelet agentsTrialsYear ContributionsSTOP-HT-2Swedish Trial in Old Pts. With HT1998Older & newer agents are effective in treating elderly HT pts.PROGRESSPerindopril Protection Against Recurrent Stroke Study2000BP reduction in post stroke pts. treated by Perindopril based

11、 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 progressTrialsYear ContributionsLIFELosartan Intervention for endpoint Reduction i

12、n HT2001Losartan vs Atendol, primary composite endpoints 25% first stroke 25% less new-onset DMALLHAT Antihypertensive therapy and lipid-lowering heart attack prevention trial2002Compare different antihypertensive drugs ANBP2Australian National BP Study 22002 comparison of ACEI & diureticsTrials

13、Year ContributionsVALUE Diovan Antihypertensive long-term Use Evaluation2004 Prompt BP 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

14、stroke Reach target is important 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 dif

15、ferent antihypertensive agents equally beneficial? Necessity of Conducting Large-scale Clinical Studies using Asian SubjectsIsolated systolic hypertension(%)0102030405001020304050(%)Systolic-diastolic hypertensionEvent Reduction in Patients on Active Antihypertensive Treatment versus Placebo or No T

16、reatmentESH-ESC Hypertension Guidelines. J Hypertens. 2003.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

17、 Randomized TrialTrialsPatientsCV EventsAll-together29162,34117,348ACEI or CA vs Placebo925,7113548More or less intensive521,9821191ARB vs Control416,7912478ACEI, CA vs D, BB16101,22810,131Meta-Analysis of Antihypertensive Treatment Trials: Effects on Major Cardiovascular EventsBPLT Trialists Collab

18、oration. Lancet. 2003;362:152735.Meta-Analysis of Antihypertensive Treatment Trials: Effects on StrokeBPLT Trialists Collaboration. Lancet. 2003;362:152735.Meta-Analysis of Antihypertensive Treatment Trials: Effects on CHD EventsBPLT Trialists Collaboration. Lancet. 2003;362:152735.Meta-Analysis of

19、Antihypertensive Treatment Trials: Effects on Heart FailureBPLT Trialists Collaboration. Lancet. 2003;362:152735.Comparisons of ARB-BasedRegimens With Control RegimensBPLT Trialists Collaboration. Lancet. 2003;362:152735.Trials Comparing Different Antihypertensive Regimens: New Onset DiabetesZanchet

20、ti, Ruilope. J Hypertens. 2002;20:2099110.Limitations 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.Most trials have recruited complicated hypertensives only. Are the results of

21、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 2004Event-Based Versus TOD-Based Trials When trials include hypert

22、ensives 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 dise

23、ase 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 2004Choice of Antihypertensive DrugsDifferences in some effect or in some group of patients may exi

24、st 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

25、 ACEI more effective than D on carotid atherosclerosis Drugs are not equal in terms of adverse disturbancesConfirmation of previous WHO-ISH guidelines: the main benefits of antihypertensive therapy are due to lowering BP per seESH-ESC Hypertension guidelines J Hypertens 2003Trials Comparing Differen

26、t Active Antihypertensive Agents is DifficultBecause: 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 lev

27、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-scale Clinical Studies using Asian SubjectsMorbidity & Mortality of CVD in Asian Countri

28、esMortality in China, Japan, UK, USAWHO statisticsOtherOtherOtherOtherStrokeStrokeCHDCHDCVDMortality 1/100000 Male 35-740 05005001000100015001500China UrbanChina UrbanChina RuralChina RuralUSAUSAUKUKJapanJapan 0 0200200400400600600800800China UrbanChina UrbanChina RuralChina RuralJapanJapanUKUKUSAUS

29、ACHDCHDStrokeStrokeOther CVDOther CVDOtherOtherMortality 1/100000 Female 35-74WHO statisticsMortality in China, Japan, UK, USAPast Large-scale Clinical Studies on Asian PeopleSample sizeFUyrs.BP End PointSyst.-China2,39439/4 Total/CVD/Stroke MortalitySTONE1,6323Events 59% PATs5,66525/3 Stroke recurr

30、ence 29% PROGRESS1,520+8154.59/4 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, o

31、r 55 death. The benefit was particularly evident in diabetic pts. Effects of Antihypertensive Treatment in 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 = Control73731361361031032012013636161635351515139

32、1391741741711712762761391391711711181181331330 0100100200200300300400400500500StrokeStrokeCHDCHDCardiovasCardiovasVascularVascularOthersOthersFatal eventsFatal eventsNon-fatal eventsNon-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 A

33、sian People?ALLHAT Long acting CCBs are safe BP lowing is most important Combination therapy is often necessary Amlodipine is the first choice for preventing strokeVALUE: Main ResultsGood BP control was achieved with both treatment regimens, but BP decrease in the amlodipine group was more pronounce

34、d, particularly early in the trialDespite BP differences, the primary composite cardiac endpoint in both groups was not differentJulius 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 sign

35、ificantly 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 groupJulius S et al. Lancet. June 2004;363. The observed difference in

36、 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 controlVALUE: InterpretationsJu

37、lius 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 investigationJulius S et al. Lance

38、t. 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 trialVALUE: ImplicationsJulius S et al. Lancet. June 2004;363. Prompt blood

39、 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 controlVALUE: ConclusionsJulius S et al. Lancet. June 2004;363.What do We Expect for Future Large-s

40、cale 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 trialsThank You ! Is an

41、tihypertensive 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 benef