从最新临床研究看常见高血压病人的治疗策略

从最新临床研究看常见,高血压病人的治疗策略,IHDIschemic Heart Disease,Prospective Studies Collaboration.,Lancet,. 2002;360:1903-1913.,收缩压,舒张压,Usual Diastolic BP (mm Hg),50-59 years,60-69 years,70-79 years,80-89 years,Age at risk:,40-49 years,256,128,64,32,16,8,4,2,1,0,80,90,100,110,70,IHD Mortality(Floating Absolute Risk and 95% CI),Usual Systolic BP (mm Hg),50-59 years,60-69 years,70-79 years,80-89 years,Age at risk:,40-49 years,256,128,64,32,16,8,4,2,1,0,120,140,160,180,血压、年龄与冠心病死亡率(100万人群资料分析),降压治疗的绝对收益*,（降幅,10/5,mmHg,与,20/10,mmHg 的,比较）,危险分层,绝对危险,(,10,年,CVD,危险),绝对收益,(每治疗,1000,人年预防,CVD,事件),10/5 mmHg,20/10 mmHg,低危,15%,5,10,17,Blood Pressure Lowering Treatment Trialists Collaboration,BPLTTC,协作研究,Second cycle of overview analyses,（2003）,Institute,for,International,Health,代表广泛患病人群,样本量：162,341 人,平均年龄 65 岁，男性占 52 ,平均随访 2-8 年,随访 700000 人年,权威公正,得到WHO-ISH的支持，澳大利亚官方资助,BPLTTC协作研究:,前瞻性荟萃分析,0.5,1.0,2.0,相对危险,RR (95% CI),BP,差异,(mm Hg),主要心血管事件,心血管死亡率,总死亡率,1.02 (0.98, 1.07),2/0,ACEI vs D/BB,1.03 (0.95, 1.11),2/0,ACEI vs D/BB,1.00 (0.95, 1.05),2/0,ACEI vs D/BB,1.04 (0.99, 1.08),1/0,CA vs D/BB,1.05 (0.97, 1.13),1/0,CA vs D/BB,0.99 (0.95, 1.04),1/0,CA vs D/BB,0.97 (0.92, 1.03),1/1,ACEI vs CA,1.03 (0.94, 1.13),1/1,ACEI vs,CA,1.04 (0.98, 1.10),1/1,ACEI vs,CA,Blood Pressure Lowering Treatment Trialists Collaboration.,Lancet,. 2003;362:1527-1535.,BP-Lowering Treatment Trialists,Collaboration,不同活性治疗药物的比较,有利于前者,有利于后者,降压治疗的收益主要来自降压本身,高血压治疗的主要目的是最大限度地降低心血管发病和死亡的总危险,降压治疗的收益主要来自降压本身,目前高血压治疗中的新问题及思考,1、选择降压药物时，是将降压能力还是将降压外作用做为选择标准？,2、降压达标应该多早？数天、数周还是数月？,3、大多数高血压病人需要联合用药，何种联合用药方案更有利于血压降低及减少终点事件？,最新高血压临床研究带来的启示,VALUE,ASCOT-BPLA,ASCOT-LLA,VALUE:,头对头研究设计,选择性加量至目标,BP (140/90 mmHg),Month0.5 0 1 2 3 4 6 * 72,A 10 mg +HCTZ 25 mg,A 5 mg,A 10 mg +HCTZ 12.5 mg,A 10 mg,V 80 mg,V 160 mg,V 160 mg +HCTZ 12.5 mg,V 160 mg +HCTZ 25 mg,氨氯地平组,V 160 mg +HCTZ 25 mg + Free add-on,A 10 mg +HCTZ 25 mg + Free add-on,缬沙坦组,筛选,随机,End of treatment adjustment period,Rolloverfromprevious therapy(92%),*Patient visits every 6 months for months 672.,Julius S et al.,Lancet,. June 2004;363.,Julius S et al.,Lancet,. June 2004;363.,缬沙坦 (N= 7649),氨氯地平 (N = 7596),135,140,145,150,155,mmHg,月,(或终末随访),治疗组随时间变化的坐位收缩压,Baseline,1,24,48,2,3,4,6,12,18,30,36,42,54,60,66,0,1.0,2.0,3.0,4.0,1,24,48,mmHg,2,3,4,6,12,18,30,36,42,54,60,66,月,5.0,缬沙坦与氨氯地平SBP的差异,1.0,(或终末随访),VALUE: 氨氯地平早期和持久的血压控制能力明显优于ARB,有利于缬沙坦,有利于氨氯地平,危险比,缬沙坦/,氨氯地平,主要心脏终点,心脏病发病,心脏病死亡,全部心梗,全部充血性心衰,全部脑卒中,所有原因所致死亡,新发糖尿病,0.5,1,2,整体研究预先设定终点的分析,Julius S et al.,Lancet,. June 2004;363.,VALUE:根据6个月时血压控制情况的结果分析,致死/非致死性心脏事件,致死/非致死脑卒中,全因死亡,心肌梗死,心衰住院,*SBP 140 mmHg at 6 months.,*,P, 0.01.,缬沙坦组患者,氨氯地平组患者,Hazard Ratio 95% CI,0.4,0.6,0.8,1.0,1.2,血压达标患者*,(n = 5253),血压未达标患者,(n = 2396),*,*,*,*,0.4,0.6,0.8,1.0,1.2,血压达标患者*,(n = 5502),血压未达标患者,(n = 2094),Hazard Ratio 95% CI,*,*,*,*,0.76 (0.660.88),0.60 (0.480.74),0.79 (0.690.91),0.83 (0.661.03),0.62 (0.500.77),Odds Ratio,0.73 (0.630.85),0.50 (0.390.64),0.79 (0.690.92),0.91 (0.711.17),0.64 (0.520.79),Odds Ratio,Weber MA et al.,Lancet.,2004;363:204749.,VALUE: 根据1个月内降压效应的结果分析,致死/非致死性心脏事件,致死/非致死性脑卒中,全因死亡,心肌梗死,心衰住院,0.4,0.6,0.8,1.0,1.2,1.4,早期降压有效患者*,(n = 9336),非早期降压有效患者,(n = 5663),Odds Ratio 95% CI,*Those not on previous tx: SBP, 10 mmHg at one month;,those on previous tx: SBP baseline at one month.,*,P, 0.05;,P, 0.01.,Pooled Treatment,Groups,*,*,0.88 (0.790.97),0.83 (0.710.98),0.90 (0.810.99),0.89 (0.761.04),0.87 (0.751.01),Odds Ratio,Weber MA et al.,Lancet.,2004;363:204749.,VALUE:,早期血压控制带来更多的心血管获益,时间段,(月),整个研究,3648,2436,1224,612,03,研究结束,有利于氨氯地平,1.0,2.0,0.5,主要终点,风险比 和,95%,可信度区间,两组SBP差异,mmHg,1.4,1.6,1.8,2.0,3.8,1.7,2.2,36,2.3,有利于缬沙坦,4.0,Julius S et al.,Lancet,. June 2004;363.,VALUE: 结论,高危高血压患者,及早积极,控制血压达标至关重要,Julius S et al.,Lancet,. June 2004;363.,“这些发现提示控制BP达到推荐的目标应在相对短的时间内实现,（数周，而非数月）,，至少对于高危高血压患者应如此。”,Julius, VALUE研究小组,Syst-Eur,随访期延长研究也证明了,早期降压达标有更多的长远获益,16,Dec,1988,31,Jan,1990,14,Feb,1997,31,Dec,2001,intention-to-treat-analysis,RUN-IN,SINGLE-,BLIND,DOUBLE-BLIND,EXTENDED FOLLOW-UP*,OPEN FU,OPEN FU,non-supervised,supervised,supervised,non-supervised,active,active,placebo,placebo,active,*,Follow-up visits at 3-month (first year) or 6-month intervals.,Syst-Eur,结果：,SBP,n =,n =,2297,2398,1600,1688,1086,1123,732,783,497,527,Years since randomisation,0,1,2,3,4,1691,1825,1660,1789,1533,1680,1445,1560,1336,1441,Years of extended follow-up,0,1,2,3,4,SBP,(mmHg),180,170,160,150,140,target,160.2,173.8,149.6,151.0,141.7,160.4,142.1,Placebo,Active,Active,Active,Double-blind trial,Follow-up Study,Syst-Eur,结果：致死和非致死性脑卒中,8,6,4,2,0,8,6,4,2,0,30%,Strokes per 100 patients,Total follow-up,Median FU: 6 years,Double-blind trial,Median FU: 2 years,0,1,2,3,4,Years since randomisation,Placebo,Active,Placebo,Active,Active,Active,p=0.002,42%,0,2,4,6,8,1,3,5,7,p=0.006,*,N = 4695,小结,降压药物的降压能力应该做为选择降压药物的主要标准,长期持久控制血压,早期控制血压,长效CCB氨氯地平早期及持久控制血压能力优于ARB缬沙坦,如何提高降压达标能力？,降压达标是关键，一种药仅使3060患者达标,2级高血压以上或高于目标值20mmHg以上的患者，常需要联合用药,Chin J hyper vol 12 No.6 487-489,2004年中国高血压防治指南,利尿剂,b,-,阻滞剂,ARB,a,-,阻滞剂,钙拮抗剂,ACEI,合理的降压联合治疗方案,但何种联合方案最佳？国内外的指南都没有明确,欧洲最大的高血压研究,第一个比较不同降压联合用药方案的高血压研究,探讨高血压患者加用他汀降脂治疗是否能得到更多的益处,B. Dahlof,P. Sever, N. Poulter, etc. for the ASCOT investigators. Lancet 2005; 366:895-906,ASCOT,研究设计,氨氯地平 培哚普利,阿替洛尔 ,苄氟噻嗪,19,257 名,高血压患者,PROBE,设计,ASCOT-BPLA,研究者主导, 国际多中心参与,随机、对照研究,安慰剂,阿托伐他汀,10,mg,双盲,ASCOT-LLA,10,305 患者,TC 6.5 mmol/L (250 mg/dL),Dahlf B et al. Lancet 2005:366;895-906 (,O,nline,S,ept 4, 2005),治疗方案的血压目标值, 140/90 mm Hg,或糖尿病病人 130/80,mm Hg,氨氯地平 5-10,mg,阿替洛尔 50-100,mg,培哚普利 4-8,mg,苄氟噻嗪,1.25-2.5 mg,多沙唑嗪,GITS 4-8 mg,add,add,add,其他可添加药物,如,moxonidine/spironolactone,add,Dahlf B et al. Lancet 2005:366;895-906 (,O,nline,S,ept 4, 2005),ASCOT-BPLA,：,氨氯地平为基础的降压方案早期和持久血压控制优于对照组,mm Hg,60,80,100,120,140,160,180,Time (years),Baseline,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,阿替洛尔,苄氟噻嗪,氨氯地平,培哚普利,137.7,136.1,79.2,77.4,平均血压差异,1.9,Last visit,平均血压差异,2.7,SBP,DBP,163.9,164.1,94.8,94.5,Dahlf B et al. Lancet 2005:366;895-906 (,O,nline,S,ept 4, 2005),所有终点总结,The area of the blue square is proportional to the amount of statistical information,氨氯地平,培哚普利更好,阿替洛尔, 苄氟噻嗪更好,0.50,0.70,1.00,1.45,主要终点,非致死性MI(包括症状MI)+致死性冠心病,次要终点,非致死性,MI(,除外无症状,MI)+ 致死性冠心病,总的冠心病终点事件 总的心血管病事件和操作总死亡率,心血管病死亡率,致死性和非致死性脑卒中,致死性和非致死性心力衰竭,3,级终点,无症状,MI,不稳定心绞痛慢性稳定心绞痛,外周动脉疾病威胁生命的心律失常,新发糖尿病新发肾功能损伤,事后分析,主要终点+冠心病血管重建治疗,心血管病死亡+心肌梗死+脑卒中,2.00,Unadjusted Hazard ratio (95% CI),0.90 (0.79-1.02),0.87 (0.76-1.00),0.87 (0.79-0.96),0.84 (0.78-0.90),0.89 (0.81-0.99),0.76 (0.65-0.90),0.77 (0.66-0.89),0.84 (0.66-1.05),1.27 (0.80-2.00),0.68 (0.51-0.92),0.98 (0.81-1.19),0.65 (0.52-0.81),1.07 (0.62-1.85),0.70 (0.63-.078),0.85 (0.75-0.97),0.86 (0.77-0.96),0.84 (0.76-0.92),Dahlf B et al. Lancet 2005:366;895-906 (,O,nline,S,ept 4, 2005),0.60,0.70,0.80,0.90,1.00,1.50,The area of the black square is proportional to the amount of statistical information,氨氯地平,培哚普利更好,阿替洛尔,苄氟噻嗪更好,p value,0.02830.0001,0.00010.0030,0.01620.0001,0.00010.0227,0.00150.0001,0.00560.0001,0.00190.0001,0.00010.0055,0.00150.0002,60,years),年轻人 (60,years),女性男性,左室肥厚（根据,ECG or ECHO）,无左室肥厚（根据,ECG or ECHO）,原先有血管病变原先无血管病变,肾功能不全无肾功能不全,有代谢综合症无代谢综合症,所有病人,亚组人群全部心血管事件和操作,Dahlf B et al. Lancet 2005:366;895-906 (,O,nline,S,ept 4, 2005),ASCOT的主要亮点,ASCOT是冠心病一级预防的研究，针对临床常见高血压伴心血管危险因素的病人,ASCOT是第一次新型降压联合方案全面胜出传统降压方案的高血压临床研究,是第一个心血管死亡率和全因死亡率出现明显差别的大型活性药物对照的临床研究,15个预设终点10个明显有利于新药方案,各个亚组人群结果与整体研究结果高度一致,国际学术界的争论,Prof Jan Staessen为代表的专家认为对于高危病人血压2.7/1.9mmHg的差别足够解释ASCOT研究终点事件的差异,ASCOT-BPLA的研究者Neil Poulter认为，两组之间诊所血压和其它心血管危险因素的差异只能解释约50%终点事件的差异,降压外作用可能对终点事件起到一定作用,不同部位的血压水平有所不同,主动脉,肱动脉,20,10,0,Fall in,Systolic,Pressure,mmHg,B,B,B,B,A,A,A,A,ACEI,b Blockers,CaB,Diur,15,Fall in,Pulse,Pressure,mmHg,10,5,0,B,B,B,B,A,A,A,A,ACEI,b Blockers,CaB,Diur,*,*,*,Fall in systollc blood pressure in,the brachial artery (B) and aortic root (A),(second peak) and the fall in pulse pressure at the two sites with the different drug classes. *P.05 compared with brachial artery values.,Morgan T. Am J Hypertens 2004;17:118-123,不同的药物对不同部位血压影响不同,CAF:,肱动脉和中心动脉,收缩压,肱动脉收缩压,平均差异(AUC)=0.7mmHg,133.9,133.2,氨氯地平,阿替洛尔,P=0.07,125.5,121.2,P0.0001,0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 AUC,115,140,135,130,125,120,mm Hg,中心动脉收缩压,平均差异(AUC)=4.3mmHg,时间(年),阿替洛尔,86 243 324 356 445 372 462 270 339 128 85 1031,氨氯地平,88 248 329 369 475 406 508 278 390 126 101 1042,ASCOT-LLA：降压基础上加用他汀有进一步获益,主要终点：非致死性心梗和致死性冠心病,0,1,2,3,4,0.0,0.5,1.0,1.5,2.0,2.5,3.0,3.5,随访年数,累积事件发生率（）,降压治疗+ 阿托伐他汀 10 mg,降压治疗+ 安慰剂,p=0.0005,36%,3.3年,由于主要终点在很早就出现了非常显著的差异，,调脂部分比计划提前近2年结束,Sever PS, et al, Lancet. 2003;361:1149-58,ASCOT的重要启示,第一次为临床选择优化降压方案提供了循证医学证据,无冠心病的高血压患者可以从以长效CCB氨氯地平为基础必要时联合ACEI的方案中获得更大益处,不但早期而且长期持久降压达标,不但降低外周血压，而且显著降低中心动脉压,对病人糖脂代谢无不良影响,在降压基础上加用他汀可以使病人获得更大益处,VALUE、ASCOT入组的都是临床常见的高血压病人高血压伴常见危险因素,VALUE研究,ASCOT研究,中国高血压指南高血压药物治疗,治疗总目标：,通过降压治疗使高血压患者的血压达标,，以期降低心脑血管病和肾病死亡率及患病率。,治疗策略,：,大多数慢性高血压病人应在,数周内,降低血压至目标水平。, 推荐用,一天一次给药而持续,24h,作用,的药物。,根据基线血压水平，有无靶器官损害和危险因素，选用单药或,联合治疗,。,常见高血压病人的治疗策略总结,最新高血压临床研究带来的启示,选择降压药物的主要标准降压达标能力,早期,持久,平稳,有效降低中心动脉压,合理的降压治疗联合策略,长效CCBACEI他汀类药物,ASCOT,ASCOT,VALUE,CAF,氨氯地平（络活喜）,高血压治疗基础用药！,谢 谢！,