高血壓的治療新的循環(huán)醫(yī)學(xué)證據(jù)

高血壓的治療新的循環(huán)醫(yī)學(xué)證據(jù)第1頁(yè)/共37頁(yè)高血壓治療：新的循證醫(yī)學(xué)證據(jù)ADVANCE研究—

固定復(fù)方制劑VALIDD研究—

降壓與心室舒張功能Ameta-analysisofRCTs中國(guó)人高血壓臨床試驗(yàn)證據(jù)第2頁(yè)/共37頁(yè)ADVANCE研究:

在11,140例2型糖尿病患者中進(jìn)行的降壓與強(qiáng)化血糖控制的析因隨機(jī)臨床試驗(yàn)培哚普利吲達(dá)帕胺固定復(fù)方制劑（百普樂(lè)）對(duì)重要血管事件的影響第3頁(yè)/共37頁(yè)Inclusioncriteria

Type2diabetesmellitusAge55yearsorolderAdditionalriskofvasculareventAge65yearsHistoryofmajormacrovasculardiseaseHistoryofmajormicrovasculardiseaseFirstdiagnosisofdiabetes>10yearspriortoentryOthermajorriskfactorHypertensiveornormotensive第4頁(yè)/共37頁(yè)RandomisedstudytreatmentsBloodpressureloweringDouble-blindperindopril-indapamideversusmatchingplacebo2.0/0.625mgorplaceboforfirst3months4.0/1.25mgorplacebothereafterBloodglucoselowering(ongoing)Open-labelgliclazideMR-basedintensivetherapytargetinganHbA1cof6.5%versususualguideline-basedcare第5頁(yè)/共37頁(yè)Amongpatientswithdiabetes,doesbloodpressureloweringtherapy:Produceadditionalbenefitswhensystolicpressureisloweredbelow145mmHg?Producesimilarbenefitsforhypertensiveandnon-hypertensivepatients?AddtothebenefitsproducedbyothercardiovascularpreventivetherapiesincludingACEinhibitors?ADVANCEstudyhypotheses

Perindopril-indapamidearm第6頁(yè)/共37頁(yè)ADVANCE

Trialprofile12877withtype2diabetesregistered11140randomised5569assignedperindopril-indapamidecombination1737withdrewduringrun-inScheduledendoffollow-up:4.3years4908(88%)assessedatfinalvisit4081(73%)adherenttotreatment4losttofollow-up11losttofollow-upScheduledendoffollow-up:4.3years4863(87%)assessedatfinalvisit4143(74%)adherenttotreatment5571assignedmatchingplacebo第7頁(yè)/共37頁(yè)血壓降低情況Δ2.2mmHg(95%CI2.0-2.4);p<0.001Δ

5.6mmHg(95%CI5.2-6.0);p<0.001DiastolicSystolic安慰劑組培哚普利/吲達(dá)帕胺組MeanBloodPressure(mmHg)65758595105115125135145155165Follow-up(Months)R6121824303642485460140.3mmHg134.7mmHgAverageBPduringfollow-up77.0mmHg74.8mmHg第8頁(yè)/共37頁(yè)全因死亡率Follow-up(months)01006121824303642485460

安慰劑組

培哚普利/吲達(dá)帕胺組Cumulativeincidence(%)Relativeriskreduction14%:95%CI2-25%p=0.0255第9頁(yè)/共37頁(yè)死亡分析心血管死亡Follow-up(months)6121824303642485460安慰劑組培哚普利/吲達(dá)帕胺組非心血管死亡Follow-up(months)6121824303642485460安慰劑組培哚普利/吲達(dá)帕胺組相對(duì)危險(xiǎn)降低18%;p=0.027相對(duì)危險(xiǎn)降低8%;p=0.415%5%Cumulativeincidence(%)第10頁(yè)/共37頁(yè)Coronaryevents*2P=0.02?Non-fatalMIordeathfromcoronaryheartdisease?Unstableanginarequiringhospitalisation,coronaryrevascularisationorsilentMIMajorcoronaryheartdisease?26529411%(-6to24)Allcoronaryheartdisease468535

14%(2to24)Othercoronaryheartdisease?28332414%(-1to27)*NumberofeventsPer-IndPlacebo(n=5,569)(n=5,571)Relativeriskreduction(95%CI)FavoursPer-IndFavoursPlaceboHazardratio0.51.02.0第11頁(yè)/共37頁(yè)CerebrovasculareventsMajorcerebrovasculardisease?2152182%(-18to19)Allcerebrovasculardisease2863036%(-10to20)Othercerebrovasculardisease?799921%(-6to41)2.0**2P=0.40?Non-fatalstrokeordeathfromcerebrovasculardisease?TransientischaemicattackorsubarachnoidhaemorrhageNumberofeventsPer-IndPlacebo(n=5,569)(n=5,571)Relativeriskreduction(95%CI)FavoursPer-IndFavoursPlaceboHazardratio0.51.0第12頁(yè)/共37頁(yè)Renalevents2.0Hazardratio0.51.0Neworworseningnephropathy18121618%(-1to32)Newmicroalbuminuria1094131721%(14to27)Totalrenalevents1243150021%(15to27)**2P=<0.01NumberofeventsPer-IndPlacebo(n=5,569)(n=5,571)Relativeriskreduction(95%CI)FavoursPer-IndFavoursPlacebo第13頁(yè)/共37頁(yè)經(jīng)過(guò)5年治療可預(yù)防事件數(shù):每治療患者例數(shù)1例主要血管事件66例1例死亡79例1例冠脈事件75例1例腎臟事件*20例*多為新發(fā)微量白蛋白尿常規(guī)使用培哚普利與吲達(dá)帕胺的絕對(duì)獲益第14頁(yè)/共37頁(yè)總結(jié)2型糖尿病患者常規(guī)使用培哚普利/吲達(dá)帕胺治療的結(jié)果:總死亡率降低14%心血管死亡降低18%主要血管事件降低9%總冠脈事件降低14%總腎臟事件降低21%這些獲益在所有主要亞組都相似。治療的耐受性非常好，副作用很少，遵從治療的情況與安慰劑組相似。第15頁(yè)/共37頁(yè)Amongpatientswithdiabetes,doesbloodpressureloweringtherapy:Produceadditionalbenefitswhensystolicpressureisloweredbelow145mmHg?Producesimilarbenefitsforhypertensiveandnon-hypertensivepatients?AddtothebenefitsproducedbyothercardiovascularpreventivetherapiesincludingACEinhibitors?Bloodpressureloweringindiabetes:

Unresolvedissues2000YESYESYES第16頁(yè)/共37頁(yè)VALIDD研究TheInfluenceofAngiotensinReceptorBlockersandBloodPressureLoweringonDiastolicFunctioninPatientswithHypertensionandDiastolicDysfunction:TheVALsartanInDiastolicDysfunction

血管緊張素受體拮抗劑(ARB)對(duì)高血壓和舒張功能不全患者的作用

SolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第17頁(yè)/共37頁(yè)研究目的目的:驗(yàn)證下列假說(shuō)是否正確“ARB較其他非阻斷RAAS系統(tǒng)的降壓藥物更有效改善左室舒張功能”？SolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第18頁(yè)/共37頁(yè)研究設(shè)計(jì)482例初選患者年齡大于45歲、1、2級(jí)高血壓、無(wú)心功能不全病史組織多普勒檢查，評(píng)價(jià)心肌舒張速度，確定舒張功能不全的存在384例舒張功能不全的患者纈沙坦組(n=186)320mg/d非RAAS拮抗劑降壓治療(n=198)鈣拮抗劑、利尿劑、?阻滯劑隨機(jī)分組觀察終點(diǎn)38周前后的舒張速度、等容舒張時(shí)間（S’)、加速時(shí)間、E/A、E/E’左室容積質(zhì)量、射血分?jǐn)?shù)隨訪38周SolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第19頁(yè)/共37頁(yè)ARBvs.非RAAS阻斷劑組:降壓幅度相當(dāng)38周后,兩組的血壓較基線相比降低幅度沒(méi)有顯著差異收縮壓較基線的改變(mmHg)纈沙坦組(n=186)非RAAS阻斷劑組(n=198)p=NS

SolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第20頁(yè)/共37頁(yè)ARBvs.非RAAS阻斷劑組:改善舒張功能療效相當(dāng)38周后,ARB和非RAAS阻斷類降壓藥物均顯著改善舒張功能，療效相當(dāng)時(shí)間/治療前后的變化心肌舒張速度(cm/s)纈沙坦(n=186)非RAAS阻斷劑組(n=198)基線7.57.5治療38周后8.1*8.0*心肌舒張速度提高0.66**0.44*每組治療前后比較P<0.0001,**組間比較P=NSSolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第21頁(yè)/共37頁(yè)研究結(jié)論輕中度高血壓患者雖然左室肥厚發(fā)生率低，但已經(jīng)存在心肌舒張功能不全，這是高血壓靶器官受累的早期標(biāo)志，進(jìn)而將導(dǎo)致左室肥厚在降壓療效相同時(shí)，ARB和非RAAS阻斷類降壓藥物均顯著改善心肌舒張功能，療效相同降壓治療帶來(lái)又一項(xiàng)收益，即改善舒張功能。即便是輕中度高血壓患者，也可受益SolomonS.AmericanCollegeofCardiology2007ScientificSessions,March25,2007.第22頁(yè)/共37頁(yè)VALIDD評(píng)論50%高血壓患者存在舒張功能不全，雖然部分患者最終進(jìn)展為心衰，但是迄今仍然沒(méi)有具備針對(duì)性的治療方法。VALIDD研究證實(shí)降低血壓可有效改善舒張功能不全，即使輕中度高血壓患者也可獲益。這一結(jié)果說(shuō)明：對(duì)于高血壓患者，應(yīng)該采取積極降壓措施－－DrScottSolomon，VALIDD研究領(lǐng)導(dǎo)人，布萊根女子醫(yī)院，哈佛醫(yī)學(xué)院第23頁(yè)/共37頁(yè)P(yáng)reventionofstrokeandMIbyamlodipineandARBs氨氯地平與ARBs預(yù)防卒中與心肌梗死Ameta-analysisofRCTs隨機(jī)對(duì)照臨床試驗(yàn)綜合分析WangJGetal.Hypertension2007;50:333-339.第24頁(yè)/共37頁(yè)氨氯地平vs.ARBs*:

腦卒中氨氯地平較好ARBs較好IDNTVALUECASE-J所有試驗(yàn)p=0.4630/579322/764960/2354412/10,58218/567281/759647/2349346/10,512–15.9%(6.2)2p=0.020.51.01.52.0*厄貝沙坦、纈沙坦、坎地沙坦ARBs氨氯地平試驗(yàn)事件數(shù)/研究對(duì)象人數(shù)異質(zhì)性檢驗(yàn)危險(xiǎn)比(95%可信區(qū)間)差別(SD)WangJGetal.Hypertension2007;50:333-339.第25頁(yè)/共37頁(yè)IDNTVALUECASE-JAlltrialsp=0.4051/579369/764917/2354437/10,58233/567281/759618/2349332/10,512–16.7%(6.1)2p=0.010.51.01.52.0氨氯地平vs.ARBs*:MIARBs試驗(yàn)事件數(shù)/研究對(duì)象人數(shù)異質(zhì)性檢驗(yàn)危險(xiǎn)比(95%可信區(qū)間)差別(SD)氨氯地平氨氯地平較好ARBs較好*厄貝沙坦、纈沙坦、坎地沙坦WangJGetal.Hypertension2007;50:333-339.第26頁(yè)/共37頁(yè)-1012345-21.41.21.00.80.60.4SCOPEn=4937Difference(referenceminusexperimental)inSBP(mmHg)

腦卒中Oddsratio(experimental/reference)Placebon=3279ASCOTn=19,257ACEIsn=19,438ARBsn=21,094ALLHAT/Diun=24,303LIFEn=9193Ena/Nitn=1602Amlodipinen=21,094Placebon=266111%WangJGetal.Hypertension2007;50:333-339.第27頁(yè)/共37頁(yè)-1012345-21.41.21.00.80.60.4SCOPEn=4937Difference(referenceminusexperimental)inSBP(mmHg)

心肌梗死Oddsratio(experimental/reference)Placebon=3279ASCOTn=19,257ACEIsn=19,438ARBsn=21,094ALLHAT/Diun=24,303LIFEn=9193Ena/Nitn=1602Amlodipinen=21,094Placebon=2661WangJGetal.Hypertension2007;50:333-339.第28頁(yè)/共37頁(yè)ImproveBPlowering,improveoutcome提高降壓質(zhì)量，改善結(jié)局第29頁(yè)/共37頁(yè)FEVER:研究設(shè)計(jì)和治療流程圖1344Z+非洛地平5mg/d+安慰劑HCTZ12.5mg/d隨訪周1-62-43-240516273849510611912121624203624482860月篩選隨機(jī)化如果BP>160/90mmHg，研究人員可根據(jù)判斷加用利尿劑或其他藥物（不包括鈣離子拮抗劑）第30頁(yè)/共37頁(yè)FEVER：SBP變化1351ZSBP(mmHg)隨訪(月)142.5137.3141.6138.1

安慰劑

非洛地平SR第31頁(yè)/共37頁(yè)FEVER：DBP變化1352ZDBP(mmHg)隨訪(月)85.082.583.982.3

安慰劑

非洛地平SR第32頁(yè)/共37頁(yè)腦卒中(致死性和非致死性)的Kaplan-Meier曲線1356Z隨訪(月)HR=0.732,