新型固定剂量降压制剂arbhctz.ppt.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!,2004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,Lewington et al.Lancet.2002;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;1:1349-1354 2.STOP.Lancet.1991;338:1281-1285 3.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,SBP Response to 2-Drug Combinations That Include or Do Not Include a Diuretic,With HCTZ,Without HCTZ,SBP 140 mmHg,%,P=0.002,Materson,et al.J Human Hypertens.1995;9:791-795.,77,46,0,20,40,60,80,100,2007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,Myocardial infarction,Heart failure,End-stage heart disease,Plaque rupture,Risk factors,HypertensionHyperlipidemiaDiabetes,Atherosclerosis,Endothelial dysfunction,Coronary arterydisease,Dilatation/Remodeling,Angiotensin II,The cardiovascular continuum,Potential effects of AT1-receptor blockade,ANG II,ANG II,ANG II,ANG II,ARB,AT1,AT2,ANG II,Vasodilation?Pathological GrowthApoptosis,VasodilationPathological growthApoptosisSodium&water retentionNeurohumoral activationReactive oxygen speciesPro-inflammatory processes,厄贝沙坦:剂量反应和耐受性,安慰剂对照试验汇总结果。*谷值坐位舒张压 90 mm Hg 或从基线下降10 mm Hg。Man in抰 Veld AJ.J Hypertens.1997;15(suppl 7):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-does Polypill vs Standard-dose Monotherapy:Effect on Systolic BP,N=108 with hypertension,drug naive;4-week treatment,Mahmud A.Feely J.Hypertension 2007:49;272-5.,0,-5,-10,-15,-20,-25,-30,Comb(n=22),Capt 100mg(n=22),Amlo 5mg(n=20),Aten 50mg(n=20),Bend 2.5mg(n=22),P0.01vs monotherapies,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”JNC 7,“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（2005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。”JNC 7,“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（2005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,Adapted from Julian Critchley A.J.H.et al.,Current Therapeutic Research 57:392-407,1996,氯沙坦+HCTZ(N=426),氨氯地平+HCTZ(N=419),*,*,*,*,基线,治疗周,Volpe et al Vol.25,No.5,2003,Page(s)1469-1489,*P0.001 vs.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（SiDBP 90 mmHg）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,HCTZ 12.5mg,复代文（缬沙坦80mg/HCTZ 12.5mg）,舒张压,收缩压,复代文（缬沙坦/氢氯噻嗪）降压疗效显著,JR Benz,HR Black,A Graff,et al，J Hum Hypertens,Dec 1998;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,et al.Blood Press2001;10:230,与基线相比血压的改变mmHg,-16,-14,-12,-10,-8,-6,-4,-2,0,HCTZ 25mg,收缩压,舒张压,复代文（缬沙坦80mg/HCTZ 12.5mg）,-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,SG Chrysant,DG Wombolt,et al.Current Therapeutic Research.1998(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,*Mean reductions from baseline at end point(12 weeks)in patients with mild to moderate essential hypertension.Mallion JM et al.Blood Press.2003;12(suppl 1):36-43.,Diovan and Co-Diovan:Dose-Responsive Efficacy,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),Kochar M et al.Am J Hypertens 1999;12:797-805.,每组患者数 n=40,安慰剂,HCTZ 12.5 mg,厄贝沙坦150 mg安搏维,厄贝沙坦 150 mgHCTZ 12.5 mg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%,(DBP85 mmHg),安博诺,150mg/HCTZ 12.5mg,(DBP90 mmHg),94.35%,Littlejohn T III et al.Clin Exp Hypertens 1999;21:1273-95.,厄贝沙坦/HCTZ（安博诺）治疗的长期治疗反应,正常化者*有反应者,*Trough SeDBP 90 mmHg正常化或较基础值下降 of 10 mmHg,0,20,40,60,80,100,80,83,81,87,90,87,患者(%),月,6,12,24,N=1,006,两制剂其血浆中厄贝沙坦经时浓度：,说明两制剂的药代动力学参数相近。且两制剂的参数Cmax、AUC0-24、AUC0-和Tmax经统计学检验均无显著性差异(P0.05)。（备注：AUC0-分别为13.021.96gh/ml和13.122.38gh/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,两制剂其血浆中氢氯噻嗪经时浓度：,说明两制剂的药代动力学参数相近。且两制剂的参数Cmax、AUC0-24、AUC0-和Tmax经统计学检验均无显著性差异(P0.05)。（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,1 Adapted from Ruilope LM et al Blood Pressure 5:32-40,19962 Adapted from JNC Arch Intern Med 157:2413-2446,1997,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,Adapted from Dahlf B J Ann Intern Med 2004;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 50 mg 9%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 82 mg 79 mg,*排除ACEIs,AIIAs,beta blockers.Dahlf B et al Lancet 2002;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 145.4 mmHg,氯沙坦 144.1 mmHg,阿替洛尔 80.9 mmHg,氯沙坦 81.3 mmHg,Dahlf B et al Lancet 2002;359:995-1003.,阿替洛尔 102.4 mmHg,氯沙坦 102.2 mmHg,Proportion of patients with first event(%),0,2,4,6,8,10,12,14,16,0,6,12,18,24,30,36,42,48,54,60,66,Adjusted Risk Reduction:13.0%,p=0.021,Time(months),Change from baseline(%)in LVH determined by electrocardiography,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,p 0.0001,p 0.0001,4.4%,10.2%,15.3%,9.0%,AtenololLosartan,Dahlf B et al.Lancet 2002;359:9951003.,LVH regression and primary endpoint,Atenolol,Losartan,CornellVoltage-Duration Product,Sokolow-LyonVoltage,Composite of CV Death,stroke and MI,LIFE 研究,VALUE:Major Study End Points in 5006 Patient Pairs(N=10,012)on Diovan-or Amlodipine-Based Therapies Using Serial Median Matching,Composite cardiac events,Stroke,Death,Myocardial infarction,Heart failure,0.6,0.8,1.0,1.2,1.4,Favours Diovan,Favours amlodipine,*P0.05.Weber MA et al.Lancet.2004;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,Julius S et al.Lancet.2004;363:2022-2031.,VALUE:Diovan-Based Therapy Significantly Reduces Risk for New-Onset Diabetes,Study Design,W0Visit 1 Enrolment of hypertensive patients untreated or uncontrolled by monotherapy,R,HCTZ:12.5 mg od-5 weeks,W4Visit 2Exclusion if SBP 140 mm Hg(office),W13Visit 4Final evaluation,5 weeks,8 weeks,Phase 1,Phase 2,COSIMA Study,COSIMA：,BP final-baseline(mm Hg),HBPM(average of all values),DBP,SBP,Office BP(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.Bobrie et al.Archives Mal Coeur Vaiss 2004(12):p96 and p116,-9.6,-7.4,-13.4,-10.6,-8.2,-6.8,-14.8,-11.6,Significantly More Patients Normalisedon Irbesartan Combination Therapy*,%Patients,P0.0001,Office,HBPM,P0.05,Normal HBPM values:SBP 135 mm Hg andDBP 85 mm Hg,Normal office values:SBP 140 mm Hg andDBP 90 mm Hg,19.6%,10.3%,Data on file,52.9%,33.3%,51.5%,41.2%,*The PP results are consistent with the ITT results8 week study,COSIMA Study,Minimum4 weeks,1,005 Uncontrolledon SingleAntihypertensiveAgent,INCLUSIVE:Study Design,Multicenter(119 sites across the US),prospective,open-label,single-arm study,Screening,Intent-to-treat(ITT)population,n=736.Week 18 aggregate data for irbesartan/HCTZ 150/12.5 mg and 300/25 mg include all patients whose BP was controlled from baseline.Entry criteria at screening were SBP 140 mmHg,130 mmHg in type 2 diabetes;entry criterion at each stage of the study was DBP 70-109 mmHg;mean DBP at baseline=91.3 mmHg.Some patients were at goal DBP at baseline.*Goal:SBP 140 mmHg,DBP 90 mmHg,except patients with type 2 diabetes:SBP 130 mmHg,DBP 80 mmHg.BP=blood pressure;DBP=diastolic blood pressure;SBP=systolic blood pressure.,DBP Goal,SBP Goal,INCLUSIVE Blood Pressure Goal Attainment at Week 18,ITT population;T2DM,type 2 diabetes mellitus,Elderly(n=184),African-American(n=157),Hispanic/Latino(n=110),T2DM(n=227),Metabolicsyndrome(n=345),Women(n=370),Men(n=366),130 mm Hg,73%,73%,72%,75%,82%,73%,56%,0,20,40,60,80,100,Patients Controlled(%),Elderly(n=184),African-American(n=157),Hispanic/Latino(n=110),T2DM(n=227),Metabolicsyndrome(n=345),Women(n=370),Men(n=366),80 mm Hg,80%,96%,78%,83%,86%,77%,63%,0,20,40,60,80,100,Patients Controlled(%),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,Adapted from:de Gasparo et al.Pharmacol Rev.2000;52:415,ACE,ARB作用示意图,血管舒张抗增殖作用凋亡,Clinical Significance of AT1 Receptor Blockade,A II,AT2,BP,Atherosclerosis,EndothelialFunction,Neuroendocrine,LVH,CardioprotectionVasculoprotectionRenoprotection,AT1 receptor blockade,A II binding at the AT2 receptor,ARB,LVH=left ventricular hypertrophy.,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,Diez et al.Circulation 2002;105:25122517.,Baseline,During Treatment,3.95,3.9,3.85,3.8,3.75,3.7,3.65,P0.001,LosartanAtenolol,LIFE 研究,Months in LIFE,Left Atria diameter(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,Adapted with permission from Tzemos N et al.Am J Hypertens.2001;14:A66-A67.0,*P 0.05 vs 基线,代文增加内皮NO的产生和释放，改善血管内皮功能,Klingbeil AU,et al.Am J Hypertens 2003;16:1238,0.6,0.4,0.2,0,0.2,代文 80 mg HCTZ 25 mg 安慰剂,NG-单甲基-L-精氨酸刺激后前臂血流量变化*(mL/min/100 mL),服用氢氯噻嗪治疗无明显变化,0.6(n=20),0.2(n=20),(n=20),p0.05 vs安慰剂,Valsartan Improves Insulin Sensitivityin Hypertensive Patients,Top C,et al.J Internat Med Res.2002;30:1520.,Normotensive(20)Hypertensive(20)Pre-TreatmentHypertensivePost-Treatment(valsartan 80 mg),Fasting Insulin(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(%),2.0,3.0,4.0,5.0,0.12,0.08,0.04,0.00,4 Months,12 Months,18 Months,24 Months,P 0.0001,P 0.001,P 0.0001,P=0.031,P 0.001,P 0.0001,P 0.0001,P=0.033,Wong M et al.J Am Coll Cardiol.2002;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,Parving H-H,et al.N Engl J Med2001;345:870-878.,0,5,10,15,20,0,3,6,12,18,22,24,随访时间(月),患者比例(%),对照组安博维 150 mg安博维 300 mg,RRR 70%P0.001,5.2%,9.7%,14.9%,70%,IRMA2:安博维使34%患者尿白蛋白排泄率恢复正常,Parving H-H,et al.N Engl J Med2001;345:870-878.,安博维,40,30,20,10,0,对照组(n=201),150 mg(n=195),300 mg(n=194),24,34,21,P=0.006,患者比例(%),IDNT:安博维显著降低到达主要终点的危险性20%,0,0,25,50,75,12,24,36,48,安博维 300mg组（n=570）,氨氯地平10mg组（n=567）,随访时间（月）,对照组（n=569）,VS,安博维,20%,p0.02,*主要终点：血清肌酐升高达2倍、终末期肾病或各种原因引起的死亡,与氨氯地平相比，安博维降低到达主要终点的危险性23%,p=0.006,治疗时间:2.6年,到达主要终点*的患者比例（）,Lewis EJ,et al.N Engl J Med(新英格兰杂志).2001;345:851-860.,60,Soffer et al.Hypertension 1995,26(1):112-117,科素亚+利尿剂（海捷亚）也不影响尿酸代谢,血清尿酸,mmol/L,*,*,*P0.01,-30,-25,-20,-15,-10,-5,0,5,10,15,氯沙坦25mg/HCTZ25mg,*,氯沙坦50mg/HCTZ25mg,氯沙坦100mg/HCTZ25mg,安慰剂/HCTZ25mg,氯沙坦平衡低剂量利尿剂对代谢影响,新型固定复方制剂中国专家共识,无并发症1、2级高血压患者，及老年收缩期高血压、合并糖尿病或代谢综合征的高血压患者，推荐ARB/HCTZ固定复方制剂。未服药的患者，ARB/HCTZ固定复方制剂可作为初始治疗。对已获得控制的高血压患者ARB/HCTZ固定复方制剂可作为维持治疗的选择药物。,降压达标需要联合治疗，联合治疗中包含HCTZ达标率高ARB单药可有效降低血压，ARB/HCTZ固定复方制剂可提高血压达标率。循证医学证实ARB单药和ARB/HCTZ固定复方制剂具有超越降压以外的降低心血管危险作用ARB/HCTZ固定复方制剂在降低血压达标及器官保护中具有重要的作用。,小 结,谢 谢,