新型固定剂量降压制剂.ppt

新型固定剂量降压制剂ARB/HCTZ临床应用的中国专家共识,北京大学人民医院孙宁玲,我们面临的巨大挑战：三高三低94%高血压患者血压不达标!,2019年中国居民营养与健康状况调查报告,三高,三低,0,5,10,15,20,25,30,35,知晓率,治疗率,控制率,百分比（）,30.2,24.7,6.1,荟萃分析61项回顾性观察研究涵盖1百万人（40-89岁）,控制心血管危险降压是关键,Lewingtonetal.Lancet.2019;360:19031913,利尿剂治疗高血压的作用1、利尿剂减轻体内钠负荷，减少钠在阻力动脉管壁中的含量，降低血管收缩的反应性。2、能增强其它降压药物的降压效应，增加血管顺应性。3、能够减轻左心室肥厚4、可弱化对低盐饮食的限制,几项主要使用利尿剂的高血压治疗研究,1.EWPHE.Lancet.1985;1:1349-13542.STOP.Lancet.1991;338:1281-12853.SHEP.JAMA.1991;265:3255-3264,EWPHE,STOP,SHEP,病例数,840,1627,4736,随访（年）,12,4,4.5,收缩压,160,180,160,-,36,-,47,-,36,心性事件减少（,%,）,-,32,-,40,-,32,平均年龄,SBPResponseto2-DrugCombinationsThatIncludeorDoNotIncludeaDiuretic,WithHCTZ,WithoutHCTZ,SBP140mmHg,%,P=0.002,Materson,etal.JHumanHypertens.2019;9:791-795.,77,46,0,20,40,60,80,100,2019年ESC/ESH降压药物的选择,降压治疗的主要获益源自降低血压本身。五大类降压药物：噻嗪类利尿剂钙拮抗剂血管紧张素转换酶(ACE)抑制剂血管紧张素受体阻滞剂(ARB)-阻滞剂,Myocardialinfarction,Heartfailure,End-stageheartdisease,Plaquerupture,Riskfactors,HypertensionHyperlipidemiaDiabetes,Atherosclerosis,Endothelialdysfunction,Coronaryarterydisease,Dilatation/Remodeling,AngiotensinII,Thecardiovascularcontinuum,PotentialeffectsofAT1-receptorblockade,ANGII,ANGII,ANGII,ANGII,ARB,AT1,AT2,ANGII,Vasodilation?PathologicalGrowthApoptosis,VasodilationPathologicalgrowthApoptosisSodium15(suppl7):S27-S33.,总的治疗反应率*%,(n=539),(n=277),(n=357),(n=216),厄贝沙坦(mg/天),扣除安慰剂作用的不良反应(%病例数),(n=641),(n=297),(n=516),(n=282),Low-doesPolypillvsStandard-doseMonotherapy:EffectonSystolicBP,N=108withhypertension,drugnaive;4-weektreatment,MahmudA.FeelyJ.Hypertension2019:49;272-5.,0,-5,-10,-15,-20,-25,-30,Comb(n=22),Capt100mg(n=22),Amlo5mg(n=20),Aten50mg(n=20),Bend2.5mg(n=22),P0.01vsmonotherapies,SBP(mmHg),单药治疗控制率低，多数使用联合治疗,“超过2/3的高血压病人需要两种或两种以上不同类别的药物而不是只用一个药物来有效控制血压”JNC7,“血压控制在140/90mmHg以内的病人中的60使用了两种或两种以上的药物，只有30的病人使用了一种药物。”ALLHAT研究,“随机临床试验证明，大多数高血压病人为控制血压须用两种或两种以上降压药”中国高血压防治指南（2019修订版）,选择药物组合有差别,ARB加小剂量利尿剂持续用药比例最高，放弃治疗或转药比例最低,100,90,80,70,60,50,40,30,20,10,0,0,3,6,9,12,15,18,21,24,27,自治疗开始的时间（月）,21%,17%,患者比率（%）,固定复方制剂2片药物同时服用,固定复方制剂较2片药物同服依从性高,复方固定复方制剂在指南中被推荐,“固定复方制剂常常在更低的组方剂量下能更好的控制血压，导致的副作用也更少”“固定复方制剂会更加方便和简化治疗方案，也会比单独处方不同的药物花费少。”JNC7,“近来多类新型降压药问世，新型固定复方制剂涌现如海捷亚等。既有不同作用机制药物对降压协同作用，也使不良反应最小化。”中国高血压防治指南（2019修订版）,新型固定复方制剂,氯沙坦/氢氯噻嗪（海捷亚）缬沙坦/氢氯噻嗪（复代文）厄贝沙坦/氢氯噻嗪（安博诺）（依伦平）,强效快速，控制血压耐受性好，与安慰剂相似独特保护,独特的脑卒中保护,新型固定复方制剂:氯沙坦/氢氯噻嗪,ARB氯沙坦+小剂量利尿剂,联合用药-降压更快速,使用海捷亚第一周即可降低SBP16mmHg,AdaptedfromJulianCritchleyA.J.H.etal.,CurrentTherapeuticResearch57:392-407,2019,氯沙坦+HCTZ(N=426),氨氯地平+HCTZ(N=419),*,*,*,*,基线,治疗周,VolpeetalVol.25,No.5,2019,Page(s)1469-1489,*P0.001vs.基线,坐位收缩压(mmHg),联合用药强效降压：,171.9,148.9,144.7,143.8,171.2,151.3,146.2,143.8,140,145,150,155,160,165,170,175,0,6,12,18,提高血压控制率,对已经用缬沙坦单药治疗失败者，海捷亚血压控制率（SiDBP90mmHg）高达72！,ARB缬沙坦+小剂量利尿剂,-8.6,-8.8,-7.2,-7.3,-11.8,-16.5,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,缬沙坦,80mg,HCTZ12.5mg,复代文（缬沙坦80mg/HCTZ12.5mg）,舒张压,收缩压,复代文（缬沙坦/氢氯噻嗪）降压疗效显著,JRBenz,HRBlack,AGraff,etal，JHumHypertens,Dec2019;12(12):861-6.,Benz在871例轻中度高血压患者中进行的双盲安慰剂对照研究,与基线相比血压的改变mmHg,复代文（缬沙坦/氢氯噻嗪）的降压疗效优于双倍剂量氢氯噻嗪,Schmidt,etal.BloodPress2019;10:230,与基线相比血压的改变mmHg,-16,-14,-12,-10,-8,-6,-4,-2,0,HCTZ25mg,收缩压,舒张压,复代文（缬沙坦80mg/HCTZ12.5mg）,-5.7,-6.8,-14.9,-11.2,Schmidt在217例轻中度高血压患者中进行的双盲安慰剂对照研究,-17.1,-15.7,-17,-11.7,-13.1,-12.8,-12.3,-12.5,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,98,周,114,周,130,周,146,周,血压下降平均值,(mmHg),收缩压,舒张压,SGChrysant,DGWombolt,etal.CurrentTherapeuticResearch.2019(59):762-772,长期服用复代文（缬沙坦/氢氯噻嗪），降压疗效稳定,Chrysant对73例服用复代文（缬沙坦/氢氯噻嗪）的原发性高血压患者（33-77岁）进行的3年降压疗效研究。无患者因药物相关副作用退出研究,*Meanreductionsfrombaselineatendpoint(12weeks)inpatientswithmildtomoderateessentialhypertension.MallionJMetal.BloodPress.2019;12(suppl1):36-43.,DiovanandCo-Diovan:Dose-ResponsiveEfficacy,ARB厄贝沙坦+小剂量利尿剂,厄贝沙坦/HCTZ（安博诺）和单个药物治疗的剂量反应,-16,-14,-12,-10,-8,-6,-4,-2,0,SeDBP变化(mmHg),KocharMetal.AmJHypertens2019;12:797-805.,每组患者数n=40,安慰剂,HCTZ12.5mg,厄贝沙坦150mg安搏维,厄贝沙坦150mgHCTZ12.5mg安博诺,-3.5,-6.2,-10.2,-15.0,降压的达标的%,0,10,20,30,40,50,60,70,80,90,100,反应率,(%),83.5%,(DBP85mmHg),安博诺,150mg/HCTZ12.5mg,(DBP0.05)。（备注:AUC0-分别为773.13127.05ngh/ml和750.26150.62ngh/ml）,国产厄贝沙坦/氢氯噻嗪（依伦平）与进口厄贝沙坦/氢氯噻嗪（安博诺）生物等效性比较,试验结果表明：受试制剂-南京正大天晴制药有限公司研制的依伦平与参比制剂赛诺菲安万特制药股份有限公司生产的安博诺具有生物等效性。,国产厄贝沙坦/氢氯噻嗪（依伦平）与进口厄贝沙坦/氢氯噻嗪（安博诺）生物等效性比较,血压下降,利尿剂或CCB,利钠和血管扩张,RAAS激活,联合治疗的机制,联合治疗,对利尿剂长期应用的担心是否增加了糖尿病的风险？是否增加了低血钾现象？,如何看待利尿剂长期应用的安全性？,海捷亚:不影响血钾/血糖代谢,1AdaptedfromRuilopeLMetalBloodPressure5:32-40,20192AdaptedfromJNCArchInternMed157:2413-2446,2019,血钾,血糖,NS,NS,12周时，矿物质参数自基线*的平均改变,-0.1,-0.2,-0.8,-0.6,-0.4,-0.2,0,自基线的平均改变值,(mmol/L),科素亚,50mg,(n=59),海捷亚,(n=55),LIFE研究中氢氯噻嗪的使用率,AdaptedfromDahlfBJAnnInternMed2019;364:413414.,使用氢氯噻嗪患者的比例,100,80,60,0,40,20,研究月份,48,60,24,36,12,0,阿替洛尔组氯沙坦组,72,N=9193,降压获益及药物本身的获益,1、强化降压达标才能获得可能的器官保护作用。2、在降压达标后不同的药物是有差别的。,LIFE:服用药物患者%,氯沙坦阿替洛尔50mg9%10%50-100mg含氢氯噻嗪在内的其它治疗*68%63%中断研究23%27%平均剂量82mg79mg,*排除ACEIs,AIIAs,betablockers.DahlfBetalLancet2019;359:995-1003.,LIFE:相似的降压效果,研究月份,收缩压,舒张压,平均动脉压,mmHg,阿替洛尔145.4mmHg,氯沙坦144.1mmHg,阿替洛尔80.9mmHg,氯沙坦81.3mmHg,DahlfBetalLancet2019;359:995-1003.,阿替洛尔102.4mmHg,氯沙坦102.2mmHg,Proportionofpatientswithfirstevent(%),0,2,4,6,8,10,12,14,16,0,6,12,18,24,30,36,42,48,54,60,66,AdjustedRiskReduction:13.0%,p=0.021,Time(months),Changefrombaseline(%)inLVHdeterminedbyelectrocardiography,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,p0.0001,p0.0001,4.4%,10.2%,15.3%,9.0%,AtenololLosartan,DahlfBetal.Lancet2019;359:9951003.,LVHregressionandprimaryendpoint,Atenolol,Losartan,CornellVoltage-DurationProduct,Sokolow-LyonVoltage,CompositeofCVDeath,strokeandMI,LIFE研究,VALUE:MajorStudyEndPointsin5006PatientPairs(N=10,012)onDiovan-orAmlodipine-BasedTherapiesUsingSerialMedianMatching,Compositecardiacevents,Stroke,Death,Myocardialinfarction,Heartfailure,0.6,0.8,1.0,1.2,1.4,FavoursDiovan,Favoursamlodipine,*P0.05.WeberMAetal.Lancet.2019;363:2047-2049.,有利于氨氯地平,VALUE:初步结果显示，与全球结果相比，亚洲人群从以缬沙坦为基础的治疗方案中获益更多。,主要终点的危险比和95%CIs总组(n=15,245)vs亚洲人群(n=441),有利于缬沙坦,风险比,0.25,0.5,1,2,4,+,#,总组主要联合终点*亚洲人群主要联合终点总组心梗亚洲人群心梗总组充血性心衰亚洲人群充血性心衰总组中风亚洲人群脑卒中总组全因死亡亚洲人群总死亡总组心源性死亡亚洲人群心源性死亡,*心源性死亡和发病率+P0.05#P=0.054,JuliusSetal.Lancet.2019;363:2022-2031.,VALUE:Diovan-BasedTherapySignificantlyReducesRiskforNew-OnsetDiabetes,StudyDesign,W0Visit1Enrolmentofhypertensivepatientsuntreatedoruncontrolledbymonotherapy,R,HCTZ:12.5mgod-5weeks,W4Visit2ExclusionifSBP140mmHg(office),W13Visit4Finalevaluation,5weeks,8weeks,Phase1,Phase2,COSIMAStudy,COSIMA：,BPfinal-baseline(mmHg),HBPM(averageofallvalues),DBP,SBP,OfficeBP(trough),DBP,SBP,P0.001,P0.01,2.8(26%),-16,-12,-8,-4,0,2.2(30%),-16,-12,-8,-4,0,P0.05,P0.01,3.2(28%),1.4(21%),G.Bobrieetal.ArchivesMalCoeurVaiss2019(12):p96andp116,-9.6,-7.4,-13.4,-10.6,-8.2,-6.8,-14.8,-11.6,SignificantlyMorePatientsNormalisedonIrbesartanCombinationTherapy*,%Patients,P0.0001,Office,HBPM,P0.05,NormalHBPMvalues:SBP135mmHgandDBP85mmHg,Normalofficevalues:SBP130mmHgintype2diabetes;entrycriterionateachstageofthestudywasDBP70-109mmHg;meanDBPatbaseline=91.3mmHg.SomepatientswereatgoalDBPatbaseline.*Goal:SBP140mmHg,DBP90mmHg,exceptpatientswithtype2diabetes:SBP130mmHg,DBP80mmHg.BP=bloodpressure;DBP=diastolicbloodpressure;SBP=systolicbloodpressure.,DBPGoal,SBPGoal,INCLUSIVEBloodPressureGoalAttainmentatWeek18,ITTpopulation;T2DM,type2diabetesmellitus,Elderly(n=184),African-American(n=157),Hispanic/Latino(n=110),T2DM(n=227),Metabolicsyndrome(n=345),Women(n=370),Men(n=366),130mmHg,73%,73%,72%,75%,82%,73%,56%,0,20,40,60,80,100,PatientsControlled(%),Elderly(n=184),African-American(n=157),Hispanic/Latino(n=110),T2DM(n=227),Metabolicsyndrome(n=345),Women(n=370),Men(n=366),80mmHg,80%,96%,78%,83%,86%,77%,63%,0,20,40,60,80,100,PatientsControlled(%),SBP亚组达标率,DBP亚组达标率,130,80,INCLUSIVE,ARB联合利尿剂的优势,血管紧张素I,血管紧张素（肝）,血管紧张素II,ARBAT1受体拮抗剂,Adaptedfrom:deGasparoetal.PharmacolRev.2000;52:415,ACE,ARB作用示意图,血管舒张抗增殖作用凋亡,ClinicalSignificanceofAT1ReceptorBlockade,AII,AT2,BP,Atherosclerosis,EndothelialFunction,Neuroendocrine,LVH,CardioprotectionVasculoprotectionRenoprotection,AT1receptorblockade,AIIbindingattheAT2receptor,ARB,LVH=leftventricularhypertrophy.,AT1,氯沙坦有效逆转向心性LVH,氯沙坦可使47.4%患者LVMI恢复正常，向心性LVH比例从38.9%降至6.7%向心性LVH的危险性比离心性LVH高,38.9%,6.7%,47.4%,CVF=9.8%,CVF=2.7%,氯沙坦抑制胶原合成和心肌纤维化,基线,氯沙坦治疗12个月,CVF=胶原容量比例,Diezetal.Circulation2019;105:25122517.,Baseline,DuringTreatment,3.95,3.9,3.85,3.8,3.75,3.7,3.65,P0.001,LosartanAtenolol,LIFE研究,MonthsinLIFE,LeftAtriadiameter(cm),3.55,3.6,3.65,3.7,3.75,3.8,3.85,3.9,3.95,4,0,12,24,36,48,60,Losartan,Atenolol,P=0.86,P=0.003,P=0.077,P=0.025,P=0.002,P=0.01,科素亚与阿替洛尔治疗对左房内径的影响,缬沙坦vs氨氯地平:缬沙坦改善内皮功能,60,40,20,0,10,30,50,70,62%*,13%,%乙酰胆碱刺激后前臂血流量的改变,缬沙坦,氨氯地平,AdaptedwithpermissionfromTzemosNetal.AmJHypertens.2019;14:A66-A67.0,*P0.05vs基线,代文增加内皮NO的产生和释放，改善血管内皮功能,KlingbeilAU,etal.AmJHypertens2019;16:1238,0.6,0.4,0.2,0,0.2,代文80mgHCTZ25mg安慰剂,NG-单甲基-L-精氨酸刺激后前臂血流量变化*(mL/min/100mL),服用氢氯噻嗪治疗无明显变化,0.6(n=20),0.2(n=20),(n=20),p0.05vs安慰剂,ValsartanImprovesInsulinSensitivityinHypertensivePatients,TopC,etal.JInternatMedRes.2019;30:1520.,Normotensive(20)Hypertensive(20)Pre-TreatmentHypertensivePost-Treatment(valsartan80mg),FastingInsulin(uIU/mL),0,65,70,75,80,85,90,95,缬沙坦,安慰剂,100,p=0.009,无事件概率(%),13.2%,一级联合终点,0,65,70,75,80,85,90,95,100,p0.00001,缬沙坦,安慰剂,27.5%,心衰再住院率,*p0.00002,无事件生存率,缬沙坦n=185,安慰剂n=181,44%,未使用ACEI组代文可使一级联合终点降低44%,Val-HeFT的主要终点事件,Val-HeFT:左室功能的超声心动指标,缬沙坦,安慰剂,LVIDd/BSA变化(cm/m2),EF变化(%),2.0,3.0,4.0,5.0,0.12,0.08,0.04,0.00,4Months,12Months,18Months,24Months,P0.0001,P0.001,P0.0001,P=0.031,P0.001,P0.0001,P0.0001,P=0.033,WongMetal.JAmCollCardiol.2019;40:970975.,Val-HeFT试验,IRMA2:安博维300mg显著降低患者发生糖尿病肾病的危险性,ParvingH-H,eta