心衰体液潴留.pptx

心衰体液潴留治疗新进展南京医科大学第一附属医院心内科李新立教授,去除体液潴留是心衰治疗第一步,急性心力衰竭伴体液潴留可选择的治疗策略,利尿剂血管扩张剂正性肌力药超滤,ESCAPE研究:利尿剂剂量和死亡率关系,住院期间利尿剂最大用量(mg),预测的,观察到的,0.0,0.1,0.2,0.3,0.4,0.5,0,100,200,300,400,500,600,700,死亡率,HasselbladV,etal.JCardFail.2005,G.MichaelFelker,ChristopherM.OConnor,EugeneBraunwaldandfortheHeartFailureClinicalResearchNetworkInvestigators,利尿剂在心衰中的效果的观察研究,Felker,G.M.etal.:Circ.HeartFail.,2(1),56-62,2009,袢利尿剂对于急性失代偿性心衰患者可能具有致命的作用.,CircHeartFail2009;2:56-62,袢利尿剂在急性失代偿性心衰中必须的?魔鬼?缺少不了的魔鬼?,RCToflowvs.normalsodiumdietinCHF,Randomisedcomparisonofnormal(120mmol/d)andlowsodium(80mmol/d)dietin232patientswithchronicsystolicHFfollowedfor6months.PrimaryendpointHFhospitalisation.,ClinicalScience(2008)114,221230,ClinicalScience(2008)114,221230,KaplanMeyercumulativeeventcurvesforthesecondaryendpoint(readmissions+mortality)inthetwogroupsduring180daysoffollow-up,急性心力衰竭伴容量超负荷症状可选择的治疗策略,利尿剂=一个离不开的魔鬼有效但可能影响肾功能血管扩张剂(奈西立肽)轻微有效ASCEND-HF研究后对安全性没有更多顾虑正性肌力药（左昔孟旦）低血压和低排出时有效如果不是以上状况则无效且安全性有问题超滤看起来是有效的,进一步的随机对照临床试验正在进行中担心对肾功能的影响血管加压素受体拮抗剂（托伐普坦）,血管加压素AVP/抗利尿激素ADH,BloodvesselsMyocardiumPlatelets,KidneyEndothelialCells,AVP,_,+,V1aReceptors,V2Receptors,IncreasingSerumOsmolalityBaroreceptorsAngiotensinII,DecreasingSerumOsmolalityBaroreceptorsNatriureticPeptides,个氨基酸的肽类激素在下丘脑分泌从垂体后叶被分泌到血液中,Datafrom72subjectswithCHFadmittedtoOmiyaMedicalCenterinJapan.NakamuraTetal.IntJCard.2006;106(2):191-195.,(n=10),(n=10),(n=19),(n=23),(n=20),血管加压素水平(pmol/L),1.7,4.9,5.5,年龄匹配对照组,NYHA,ClassI,NYHA,ClassII,NYHA,ClassIII,NYHA,ClassIV,心衰患者AVP升高与严重程度相关,P0.05,P0.001,40,30,20,10,0,左心室重构,AVP,V1a,V1a,V2,血管收缩,后负荷,前负荷,H2O潴留,低钠血症,疾病进展,AVP和慢性心衰的病理生理,目前主要普坦类药物,托伐普坦治疗心衰优势,能有效降低充血性/容量超负荷状况其效果要高于强效利尿剂对伴有低钠血症的患者尤其合适，同时能纠正低钠状况不刺激神经内分泌系统不导致电解质紊乱不影响长期生存率GuidelinesforTreatmentofAcuteHeartfailure（JCS2011）,托伐普坦心衰领域主要临床试验,ECLIPSE-单剂量血流动力学ACTIV急性心衰,60天METEOR慢性心衰,52周EVEREST急性心衰,2+年QUEST-急性/慢性心衰,14天对神经激素和肾功能的影响,单次服用托伐普坦后尿量增加和尿渗透压降低,单次口服托伐普坦后可导致尿量增加和尿渗透压降低尿量增加呈剂量相关性,ECLIPSE,尿量,尿渗透压,单次服用托伐普坦后显著降低肺毛细血管楔压和右心房压,ECLIPSE,PCWP,RAP,托伐普坦显著降低PCWP和RAP,但无量效关系降低幅度较血管扩张剂如Tezosentan，Levisomendan,nesiritide温和，所以没有低血压的副反应,8.7,18.7,20,17.8,5.4,13.2,9.1,5.5,0,10,20,%,N=8023916533011041163(20%)(22%)(37%)(46%)(51%)(68%),低钠血症、充血症状和尿素氮升高患者60天死亡率有改善,*基线时有水肿、呼吸困难和颈静脉怒张,安慰剂,托伐普坦,AdaptedfromGheorghiadeMetal.JAMA.2004;291:1963anddataonfile.,p=0.18,P.05,P.05,ACTIVEINCHF,P.05,死亡或心衰恶化时间,Log-Rank检验,托伐普坦与对照组:p=0.0272,研究时无事件发生的比例（%）,0.4,0.5,0.6,0.7,0.8,0.9,1.0,研究天数,0,28,56,84,112,140,168,196,224,252,280,308,336,364,392,420,AdaptedfromUdelsonetalJACC2007,METEOR,主要终点：入院第7日或出院日基于目测所得总体临床状况和体重综合评分,口服托伐普坦30mgQD,安慰剂QD,口服托伐普坦30mgQD,安慰剂QD,随机化,试验B,试验A,中心被分配入试验A或B,7日或出院日,住院期间每日访视直至第7日或出院日,短期临床状态试验设计,长期结局试验,Gheorghiade,etal.JCardFail.2005;11:260-269.,48小时,7天,安全性随访,口服托伐普坦30mgQD(n=2072),安慰剂QD(n=2061),随机化,1065死亡,双重主要终点:所有原因死亡率改善/非劣效性心血管死亡或心衰住院改善,Gheorghiade,etal.JCardFail.2005;11:260-269.,因心衰恶化住院,联合结局试验设计,短期：苏麦卡明显改善心衰症状,n=1835,n=1600,n=1595,P0.001,P=0.02,所有病因死亡率,TLV,PLC,Peto-PetoWilcoxonTest:P=0.68,TLV30mg,PLACEBO,ProportionAlive,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,MonthsInStudy,0,3,6,9,12,15,18,21,24,2072,1812,1446,1112,859,589,404,239,97,2061,1781,1440,1109,840,580,400,233,95,HR0.98;95%CI(.87-1.11),Meetscriteriafornon-inferiority,心血管死亡率或心衰住院率,Peto-PetoWilcoxonTest:P=0.55,TLV,PLC,ProportionWithoutEvent,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,3,6,9,12,15,18,21,24,2072,1562,1146,834,607,396,271,149,58,2061,1532,1137,819,597,385,255,143,55,HR1.04;95%CI(.95-1.14),TLV30mg,PLACEBO,MonthsInStudy,长期总体结局,Konstametal.JAMA2007,长期低钠亚组：有改善倾向,SubjectswithBaselineSodium130mEq/L(ITTPopulation),OverallCVMortality/Morbidity(ITT)HR1.04;95%CI(.95-1.14),TLV,PLC,p0.05HazardRatio:0.60395%CILimits:0.372,0.979,MonthsinStudy,0,3,6,9,12,15,18,21,24,38,23,14,12,10,7,5,3,1,54,19,13,9,8,4,2,2,2,SubjectswithBaselineSodium130mEq/L(ITTPopulation),HazardRatio:1.06595%CILimits:0.973,1.165),26,QUEST研究设计,多中心,随机,双盲,安慰剂对照加用,同时服用的利尿剂剂量恒定,托伐普坦15mg,qd,安慰剂,qd,8,10,-3,-2,-1,1,2,3,4,5,6,7,-7-4,9,1417,治疗期,移入期,住院,同时服用的利尿剂剂量恒定,筛选,知情同意,治疗后观察(随访),27,托伐普坦对于心源性水肿的有效性和安全性研究,对于慢性心衰使用利尿剂后仍然有细胞外容量超负荷患者，加用托伐普坦15mg/天，连续天，研究其有效性和安全性主要入选标准接受下面其中一种利尿剂治疗仍然有细胞外容量超负荷症状,28,体重变化,CircJ73(Suppl.1):127,2009,Day,+1,+2,随访,治疗期,0,1,2,3,4,5,6,7,ChangefromBaseline(kg),MeanS.D.,29,尿量和摄入量变化,尿量,摄水量,安慰剂(n=57),托伐普坦(n=53),Day,ChangefromBaseline(mL),0,-500,500,1,000,1,500,2,000,Day,MeanS.D.,(ObservedCases),CircJ73(Suppl.1):127,2009,30,托伐普坦的有效性,*,CircJ73(Suppl.1):127,2009,MeanS.D.,肝肿大,静静脉怒张,(n=17),(n=18),(n=27),(n=19),(ttest),安慰剂,托伐普坦,治疗末(LOCF),*,有症状的病人数,水肿,(Fishersexacttest),体重,P=0.07,P=0.03,(ttest),P=0.03,(n=36),(n=38),(ttest),(n=57),(n=53),P0.0001,*,*,-4,-3,-2,-1,0,1,2,ChangefromBaseline(kg),-6,-5,-4,-3,-2,-1,0,ChangefromBaseline(cm),-4,-3,-2,-1,0,ChangefromBaseline(cm),0,10,20,30,40,50,60,70,80,ImprovementRates(%),*,CircJ73(Suppl.1):127,2009,31,血清电解质,Time,Baseline,4-8h,24h,2-3day,7day,+2day,+7day,3,4,5,6,SerumK(mEq/L),時間,治疗期,随访,130,135,140,145,150,SerumNa(mEq/L),Na,K,MeanS.D.,托伐普坦心衰领域主要临床试验,ECLIPSE-单剂量血流动力学ACTIV急性心衰,60天METEOR慢性心衰,52周EVEREST急性心衰,2+年QUEST-急性/慢性心衰,14天对神经激素和肾功能的影响,利尿剂治疗,肾脏灌注降低,血流减少,神经激素激活,33,心衰中“医源性”心肾综合症,患病率和死亡率增加,肾功能受损,利尿剂抵抗,(pg/ml),(ng/ml/hr),服用前和服用后小时差别,n=6,Mean+SEM,*p0.05,*p0.01vs.control,#p0.01vs.Furosemide1mg/kg,0,5,10,15,0,5,10,15,0,5,10,15,0,5,10,15,0,50,100,150,200,250,0,50,100,150,200,250,0,0.1,0.2,0.3,0,0.1,0.2,0.3,托伐普坦(mg/kg),呋塞米(mg/kg),0.3,1,3,10,0.3,1,3,0,0.3,1,3,10,0.3,1,3,0,AVP,血浆肾素活性,肾上腺素,醛固酮,(pg/ml),(ng/ml),*,*,*,*,*,*,苏麦卡对血浆神经激素的作用(托伐普坦与呋塞米),托伐普坦(mg/kg),呋塞米(mg/kg),%ChangevsPlacebo,*,*,*,*,*p0.05vsPlacebo;*p0.001vsPlacebo,Costello-Boerrigteretal,AJP2005,托伐普坦和呋塞米对GFR,ERPFandRBF的影响,降低急性失代偿性心衰危险人群肾损伤的风险,YuyaMatsueJournalofCardiology61(2013)169174,急性心衰的评价以及循证治疗,JAmCollCardiol2009；53：557-73改変,对左室心衰的治疗,ACE-I或ARB阻滞剂醛固酮拮抗剂ICD*CRT+/-ICD*地高辛*外科治疗（瓣形成、左室形成）*,瘀血,限盐利尿剂CHDF*血管加压素抑制剂*,心肌缺血,抗血小板药*他汀类*血运重建*2次预防*,房颤,心率控制地高辛阻滞剂华法令节律控制*,高血压,ACE-I或ARB阻滞剂利尿剂等,患者教育,淤血：体重、水肿高血压：血压测量心功能、二尖瓣闭锁不全：心脏超声室壁运动异常、心室瘤：心脏超声缺血：心脏超声、核医学检查、导管检查等心室失同步：心电图（广幅QRS）,循证治疗,治疗对象：评价方法,循環器病診