內(nèi)科學(xué)新進(jìn)展：高血壓治療策略

1、從臨床試驗(yàn)到臨床實(shí)踐高血壓治療策略 2015,單純收縮期高血壓,(%),(%),腦卒中,冠心病,總死亡,心血管 死亡,非心血管 死亡,致死和致殘事件,死亡率,收縮壓和舒張壓均升高的高血壓,腦卒中,冠心病,總死亡,心血管 死亡,非心血管 死亡,致死和致殘事件,死亡率,降壓治療的臨床獲益,ESH-ESC Hypertension Guidelines. J Hypertens. 2003.,0.01,0.01,0.001,NS,0.001,0.001,0.02,0.01,NS,0.001,SBP降低10-12mmHg,降壓治療的主要獲益來(lái)源于血壓降低本身 至少將血壓降至 SBP 140mmHg 和

2、 DBP 90mmHg 對(duì)糖尿病、冠心病、心力衰竭，慢性腎病患者 SBP 130mmHg 和 DBP 80mmHg 對(duì)老年人SBP 150mmHg和 DBP 90mmHg 仍然強(qiáng)調(diào)嚴(yán)格控制血壓,降壓治療的目標(biāo),中國(guó)高血壓指南2010,聯(lián)合降壓藥物治療為基本策略,中國(guó)高血壓患者知曉率僅30%、治療率僅25%,0,20,40,60,80,100,知曉率,治療率,知曉患者,未知曉患者,患者比例%,30.2%,24.7%,治療患者,未治療患者,中國(guó)心血管病報(bào)告2007年,2002年調(diào)查數(shù)據(jù),高血壓知曉者 的治療率,81.8%,大部分中國(guó)高血壓患者仍未降壓達(dá)標(biāo),2002年：總體達(dá)標(biāo)率僅6% ，已接受治療

3、患者的達(dá)標(biāo)率僅25%,0,20,40,60,80,100,全部高血壓患者,接受治療的高血壓患者,達(dá)標(biāo)患者,未達(dá)標(biāo)患者,患者比例%,6%,25%,中國(guó)心血管病報(bào)告2007年,達(dá)標(biāo)血壓：糖尿病或腎病患者血壓130/80mmHg，其他患者140/90mmHg,* 單因素Logistic 回歸分析結(jié)果，P0.05與1級(jí)高血壓患者相比,我國(guó)三甲醫(yī)院門診高血壓總達(dá)標(biāo)率僅為31.1%,0%,5%,10%,15%,20%,25%,30%,35%,40%,總達(dá)標(biāo)率,1級(jí)高血壓,2級(jí)高血壓,3級(jí)高血壓,31.1%,37.3%,32.6%,26.5%,中國(guó)降壓藥物治療現(xiàn)狀：聯(lián)合治療比例偏低,43.9%的患者單藥降壓

4、治療,21%起始聯(lián)合降壓或復(fù)方制劑,Target BP (mm Hg),Number of antihypertensive agents,1,Trial,2,3,4,Multiple Antihypertensive Agents Are Needed to Achieve Target BP,DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ e

5、t al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-405.,ASCOT trial：CV death + MI + Stroke,0.0,1.0,2.0,3.0,4.0,5.0,Years,0.0,0.0,2.0,4.0,6.0,8.0,10.0,氨氯地平 培哚普利 (No. of events = 796),阿替洛爾 芐氟噻嗪 (No. of events = 937),HR = 0.840 (0.760.92) p 0.0003,Number at risk 氨氯地平 培

6、哚普利96399415 9228 90078778 7655 阿替洛爾 芐氟噻嗪96189400 9152 88918629 7500,%,危險(xiǎn)降低 16%,ACCOMPLISH研究：主要終點(diǎn),累積事件率,HR (95% CI): 0.80 (0.72, 0.90),20%,第一個(gè)CV事件/死亡出現(xiàn)的時(shí)間 (天),p = 0.0002,650,526,2008年3月初步結(jié)果,ESH 2007: Possible Combinations of Different Classes of Antihypertensive Agents,-blockers,-blockers,Calciumanta

7、gonists,AT1-receptorblockers,Diuretics,ACE inhibitors,The most effective and well tolerated combinations are shown as solid lines,ESH Guidelines. J Hypertens. 2007;25:1105-1087.,ESH= European Society of Hypertension,ASH Position ArticleCombination Therapy in Hypertension,J Am Soc Hypertens 2010; 4(1

8、) : 4250,Recommendations,B = 阻滯劑；C = 二氫吡啶類鈣拮抗劑；non-DHP C = 非二氫吡啶鈣拮抗劑；D = 利尿劑；,中國(guó)高血壓指南2010降壓藥的聯(lián)合應(yīng)用,加入降壓藥的聯(lián)合應(yīng)用章節(jié)5.4.5 明確優(yōu)化的聯(lián)合治療方案的推薦 提出固定配比復(fù)方是治療的新趨勢(shì) 三藥聯(lián)合推薦：A+C+D,明確優(yōu)選聯(lián)合治療方案,CV=cardiovascular. Neal B et al. Lancet. 2000;356:19551964.,Current Antihypertensive Therapy Reduces CV Events,Average Reduction

9、in Events, %,Major CV Events,20%30%,Stroke,30%40%,CV Death,30%40%,60,40,20,0,100,80,積極控制血壓 血壓越低越好,？,Age，blood pressure and stroke,Age, blood pressure and CAD,Prospective Studies Collaboration。Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for

10、 one million adults in 61 prospective studies。Lancet 2002; 360: 190313,不同收縮壓、舒張壓及年齡人群缺血性心臟病的死亡率,Staessen JA, et al. Lancet. 2001;358:1305-15.,Difference in SBP (mm Hg),Odds Ratio,P = 0.003,0,5,10,15,20,25,- 5,1.50,1.25,1.00,0.75,0.50,0.25,SBP Reduction and CV Mortality,90,Events / 1000 Pt-Years,HOT

11、Trial: CV Events in Diabetics and NondiabeticsEffect of Diastolic Target at 4 Years,Hansson L et al. Lancet 1998;351: 1755-1762.,Diabetic Patientsn=1,501; p=0.016,85,80,90,85,80,Nondiabetic Patientsn=18,790; p=NS,24.4,18.6,11.9,9.9,10.0,9.3,RRR=51%,降壓治療血壓水平越低越好？ UKPDS 、 ADVANCE 和 ACCORD的啟示,BMJ. 2000

12、; 321,BP: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2,Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3,ACCORD trial：SBP reductions,Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death,Total Mortality,HR = 0.88 95% CI (0.73-1.06),HR = 1.07 95% CI (0.85-1.35),ACCORD trial：Out

13、comes,高血壓治療目標(biāo),主要目標(biāo)：血壓達(dá)標(biāo)，以便最大程度地降低心腦血管病發(fā)病率及死亡率； 目標(biāo)血壓：高危患者的血壓目標(biāo)證據(jù)不足。 普通高血壓患者血壓降至140/90 mmHg以下； 老年（65歲）患者的收縮壓降至150 mmHg以下； 年輕人或糖尿病、腎臟病，冠心病患者，一般降至130/80 mmHg以下； 腦卒中后一般目標(biāo)為140/90mmHg以下。 能耐受，逐步達(dá)標(biāo)。但冠心病患者舒張壓低于60mmHg時(shí)應(yīng)謹(jǐn)慎降壓。 在治療高血壓的同時(shí)，干預(yù)患者檢查出來(lái)的所有危險(xiǎn)因素，并適當(dāng)處理病人同時(shí)存在的各種臨床情況。,中國(guó)高血壓防治指南2010版,降壓藥物選擇,鈣拮抗劑、血管緊張素轉(zhuǎn)換酶抑制劑、血

14、管緊張素受體拮抗劑、噻嗪類利尿劑、受體阻滯劑 以及由這些藥物所組成的低劑量固定復(fù)方制劑均可作為高血壓初始或維持治療的藥物選擇。 聯(lián)合治療有利于血壓達(dá)標(biāo)。,中國(guó)高血壓防治指南2010版,Systolic BP in the Two Treatment Groups over the Course of the Trial,SPRINT: 強(qiáng)化降壓的臨床獲益,SPRINT: 強(qiáng)化降壓的臨床獲益,SRINT：強(qiáng)化降壓的安全性,RAS抑制不可或缺,RAAS活性增強(qiáng)導(dǎo)致心血管危險(xiǎn)增加與血壓水平無(wú)關(guān),Events per 1000 patient years,18,16,14,12,10,8,6,4,2,

15、0,低,低,高,高,正常,正常,0,1.8,7.8,5.5,8.2,17.5,RAAS 活性,無(wú)危險(xiǎn)因素,1 危險(xiǎn)因素,Alderman M et al. N Eng J Med 1991;324:10981104,即使患者的血壓已經(jīng)獲得良好控制，隨著RAAS活性增強(qiáng)，高血壓患者發(fā)生心肌梗死的危險(xiǎn)性仍顯著增加,Candido, R. et al. Circulation 2004;109:1536-1542,Diabetes-associated Atherosclerosis Is Ameliorated by RAS inhibitor than CCB,-SMA immunostaini

16、ng in sections of aorta,吳,LIFE Study： Primary Outcomes,0,6,12,18,24,30,36,42,48,54,60,66,Study Month,Proportion of patients with first event (%),Intention-to-treat,Losartan,Atenolol,2,4,6,8,10,12,14,16,Adjusted risk reduction 130%, P=0021 Unadjusted risk reduction 146%, P=0009,事件發(fā)生率（%）,ARB冠心病一級(jí)和二級(jí)預(yù)防

17、的作用,月,二級(jí)預(yù)防 非ARB,二級(jí)預(yù)防+ARB,一級(jí)預(yù)防+ARB,二級(jí)預(yù)防 非ARB 18.1% 二級(jí)預(yù)防 ARB 11.5%,一級(jí)預(yù)防 非ARB 6.7% 一級(jí)預(yù)防 ARB 3.0%,一級(jí)預(yù)防 非ARB,事件發(fā)生率（%）,高血壓患者無(wú)論是否已經(jīng)接受CCB治療，均能從ARB治療中獲益,其他 CCB+其他 纈沙坦+其他 纈沙坦+CCB,非ARB - CCB,非ARB + CCB,ARB - CCB,ARB + CCB,月,降壓治療 我們可以做得更好,積極降壓: BP 120-130/70-80mmHg,穩(wěn)妥降壓：13月內(nèi)達(dá)標(biāo),優(yōu)質(zhì)降壓：降低血壓變異，長(zhǎng)期平穩(wěn)控制血壓,聯(lián)合降壓: 基本降壓治療策

18、略,靶器官保護(hù)：RAS抑制劑不可或缺,多重危險(xiǎn)因素控制：降壓+降脂,中國(guó)冠心病死亡人數(shù)估計(jì),32%,26%,30%,Moran, BMC Public Health 2008;8:394,降壓治療血壓水平越低越好？ UKPDS 、 ADVANCE 和 ACCORD的啟示,BMJ. 2000; 321,X,1984-1999 北京人群總膽固醇水平的升高,1984 1999 1984 1999 男性 女性,TC( mmol/L),24%,24%,Circulation J Critchley, J Liu D Zhao 2004 110:1236-1244,Critchley J. Circula

19、tion, 2004;110:1236-1244,2500,膽固醇升高77%,1822例新增死亡由以下危險(xiǎn)因素的改變?cè)斐?糖尿病19% 肥胖4% 吸煙1%,醫(yī)藥治療避免了642例死亡事件,急性心梗治療41% 高血壓治療24% 二級(jí)預(yù)防11% 心力衰竭10% 阿司匹林治療心絞痛10% CABG 352:29-38.,LDL降低幅度與斑塊體積的變化,阿替洛爾 芐氟噻嗪,氨氯地平 培哚普利,19,257 高血壓病人,PROBE design,ASCOT-BPLA,ASCOT-LLA 22 Study design,安慰劑,阿托伐他汀,安慰劑,ASCOT-LLA 10305病人,阿托伐他汀,ASCOT

20、-LLA 22研究,ASCOT-LLA 22研究,ASCOT 血壓控制一致,收縮壓 (mm Hg),舒張壓 (mm Hg),基線164/95 治療后138/80 降低 26/15,LLA 結(jié)束,LLA 結(jié)束,結(jié)果,Sever PS, et al, Lancet. 2003;361:1149-58,ASCOT: 心血管死亡+心肌梗死+腦卒中,0.0,1.0,2.0,3.0,4.0,5.0,Years,0.0,0.0,2.0,4.0,6.0,8.0,10.0,氨氯地平 培哚普利 (No. of events = 796),阿替洛爾 芐氟噻嗪 (No. of events = 937),HR = 0

21、.840 (0.760.92) p 0.0003,Number at risk 氨氯地平 培哚普利 96399415 9228 90078778 7655 阿替洛爾 芐氟噻嗪 96189400 9152 88918629 7500,%,16%,ASCOT: 總膽固醇和LDL-C的降低,200,150,150,75,125,100,100,(mg/dL),(mg/dL),總膽固醇 (mmol/L),LDL-C (mmol/L),年,1.3 mmol/L,1.1 mmol/L,1.2 mmol/L,1.0 mmol/L,LLA 結(jié)束,2,4,6,0,1,2,3,他汀,安慰劑,1,2,3,4,0,1

22、,2,3,結(jié)果,Sever PS, et al, Lancet. 2003;361:1149-58,ASCOT-LLA: 他汀治療降低高血壓患者的主要轉(zhuǎn)歸終點(diǎn),Sever PS et al. Lancet. 2003;361:1149-58.,Mean baseline LDL-C 133 mg/dL Nonfatal MI and fatal CHD,Patients (%),Placebo,0,0,1,2,3,4,Statin,1.0,1.5,3.0,3.5,2.0,2.5,0.5,Follow-up (years),36% RRRHR 0.64 (0.500.83) P = 0.0005

23、,n = 10,305,ASCOT: 在降壓治療的基礎(chǔ)上，調(diào)脂治療進(jìn)一步 顯著降低總的冠心病事件達(dá)29%,降低 27%,HR = 0.73 (0.56-0.96),p=0.0236,他汀治療事件數(shù) 89 安慰劑事件數(shù) 121,Sever PS, et al, Lancet. 2003;361:1149-58,ASCOT: 在降壓治療的基礎(chǔ)上，調(diào)脂治療進(jìn)一步顯著降低27%的腦卒中,MEGA: Provastatin on CVD endpoints in HTN,Hypertension 2009;53;135-141;,- 16.4%,MEGA: Provastatin on CVD endp

24、oints in HTN,CHD,CVD events,CHD+CI,CI,Hypertension 2009;53;135-141;,*Per 1000 patient-years,Censoring time,Hazard ratio,RRR (%),Event rate*,Statin,Placebo,30 days 90 days 180 days 1 year 2 years End of study,832.414.2 675.516.6 487.514.3 456.612.0 385.99.5 366.09.4,0,0.5,1.0,1.5,2.0,Statinbetter,Pla

25、cebobetter,Sever PS et al. Am J Cardiol. 2005;96(suppl):39F-44F.,ASCOT-LLA：事后分析提示他汀治療高血壓患者個(gè)月即可顯著獲益,n = 10,305,LDL-C降低幅度與心臟事件減少（%）58項(xiàng)臨床試驗(yàn)（治療者76359；安慰者71962）,薈萃分析的結(jié)果 58項(xiàng)臨床試驗(yàn)（治療者76359；安慰者71962）,試驗(yàn)時(shí)間 危險(xiǎn)性降低（%）,降壓+調(diào)脂可預(yù)防的心血管事件比例,*,*,* p0.05, * p0.01 compared to men,(Wong et al., Am J Cardiol, June 15, 2003

26、),2007中國(guó)血脂指南： 安全有效推廣應(yīng)用他汀,當(dāng)前我國(guó)他汀應(yīng)用的問(wèn)題: 不足-應(yīng)用面不夠廣 積極 不規(guī)范-安全掌握不夠 謹(jǐn)慎 指南要求嚴(yán)格注意事項(xiàng)治療: -根據(jù)不同對(duì)象進(jìn)行危險(xiǎn)估計(jì),設(shè)定起治要求、 治療目標(biāo)值 -按降脂強(qiáng)度和安全性合理選用藥物 -達(dá)標(biāo)或降低30-40%LDL-C值 -起用前后檢查肌酶和肝酶,嚴(yán)密觀察肌肉癥狀 -合理安排劑量,不宜追求高效而盲目加大劑量,難治性高血壓：腎交感神經(jīng)消融,難治性高血壓,難治性高血壓（refractory hypertension或resistant hypertension） 凡服全劑量的三種或三種以上的不同作用機(jī)理（必須包括利尿劑）的降壓藥物，血

27、壓仍140/90mmHg 1種利尿劑，2個(gè)月治療，3藥聯(lián)合，BP140/90mmHg 發(fā)生率：5-18%；HOT研究：7% 難治性高血壓中以原發(fā)性高血壓為主(90%) 繼發(fā)性高血壓大多表現(xiàn)難治性高血壓。,難治性高血壓：原因,血壓測(cè)量不當(dāng) 容量過(guò)大(鈉鹽攝入，少尿，入液量.) 無(wú)抗高血壓治療或治療不足 其他合并使用的藥物所致 伴隨其它疾病狀態(tài) 繼發(fā)性高血壓,RENAL NERVES AS A THERAPEUTIC TARGET,Multiple Discrete TreatmentsMaximize Nerve Coverage Without Applying Circumferential

28、 Energy in a Single Segment,First-in-Man (AU),Series of Pilot Studies (EU, US eGFR 45 mL/min) - 12-month data Expanded Cohort* This Report (Symplicity HTN-1): Expanded cohort of patients (n=153) 36-month follow-up,Lancet. 2009;373:1275-1281,80,Symplicity HTN-1,*Expanded results presented at the Amer

29、ican College of Cardiology Annual Meeting 2012 (Krum, H.),Hypertension. 2011;57:911-917.,Assessed for Eligibility (n=190),Excluded During Screening, Prior to Randomisation (n=84) BP 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) Ineligible anatomy (n=30; 16%)

30、 Declined participation (n=10; 5%) Other exclusion criteria discovered after consent (n=8; 4%),Randomised (n=106),Allocated to RDN n=52 Treated n=49 Analysable,6-month Primary End-Point,Screening,Allocated to Control n=54 Control n=51 Analysable,12-month Post- Randomisation,12-month post-RDN n=47,Pe

31、r protocol, 6-mo Post-RDN (Crossover) n=35,Not-per-protocol*, 6-mo Post-RDN (Crossover) n=9,* Crossed-over with ineligible BP (160 mmHg),Symplicity HTN-2: Patient disposition,Crossover n=46,2 LTFU,RDN and Control Populations Well-matched, Severe Treatment Resistant Hypertensives,* n = 42 for RDN and

32、 n = 43 for Control. Wilcoxon rank-sum test for two independent samples used for between-group comparisons of UACR. n = 39 for RDN and n = 42 for Control.,Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.),Symplicity HTN-2: Procedural Safety,One renal ar

33、tery dissection from injection of contrast into renal artery wall during dye angiography. The lesion was stented without further consequences One hospitalization prolonged in a crossover patient due to hypotension following the RDN procedure. IV fluids administered, anti-hypertensive medications dec

34、reased and patient discharge without further incident No radiofrequency-related renal artery stenosis or aneurysm occurred in either Randomised group Minor adverse events (full cohort) 1 femoral artery pseudoaneurysm treated with manual compression 1 post-procedural drop in BP resulting in a reducti

35、on in medication 1 urinary tract infection 1 prolonged hospitalisation for evaluation of paraesthesias 1 back pain treated with pain medications and resolved after 1 month,Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.),Symplicity HTN-2: Medication Ch

36、anges at 6 and 12 Months Post-Renal Denervation,Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached*,*Further analysis of Medications is ongoing,Symplicity HTN-2: Renal Function Results,Symplicity HTN-2 Investigators. The Lancet. 2010.,RDN N=47,Crosso

37、ver N=35,Treated at Randomisation,Treated after 6-mo follow-up,Efficacy Endpoints,Primary Effectiveness Endpoint: Comparison of office SBP change from baseline to 6 months in RDN arm compared with change from baseline to 6 months in control arm Endpoint = (SBPRDN 6 month SBPRDN Baseline) (SBPCTL 6 m

38、onth SBPCTL Baseline) Superiority margin of 5 mm Hg Powered Secondary Effectiveness Endpoint: Comparison of mean 24-hour ambulatory (ABPM) SBP change from baseline to 6 months in RDN arm compared with change from baseline to 6 months in control arm Superiority margin of 2 mm Hg,Bhatt DL, Kandzari DE, ONeill WW,