高血压与降压治疗策略 中国高血压防治指南解读

1. 高血压与降压治疗策略 中国高血压防治指南解读

2. 中国高血压防治指南(2005) 血压水平分类和定义 分类 收缩压(mmHg) 舒张压(mmHg) 正常血压 < 120 和 < 80 正常高值 120-139 或 80-89 高血压  140 或  90 1级 140-159 或 90-99 2级 160-179 或 100-109 3级  180 或  110 单纯收缩期高血压  140 和 < 90

3. 60 男性 女性 合计 48.4 43.0 45 38.6 36.1 34.0 30.4 构成比例 (%) 30 15.6 13.7 15 12.3 5.8 5.1 5.4 2.5 2.4 2.4 0 正常高值 高血压I级 高血压II级 正常血压 高血压III级 中国大陆成年人群血压水平分类(2002) 卫生部心血管病防治研究中心，中国心血管病报告 2007

4. 中国大陆人群血压正常高值检出率(%) 1991(29.0%) ～ 2002(34.0%) 年龄组 1991年 2002年 18-24 25.4 28.5 25-34 26.0 30.9 35-44 30.2 36.7 45-54 32.9 38.0 55-64 32.7 34.9 65-74 31.2 30.3 75~ 28.7 28.1 卫生部心血管病防治研究中心，中国心血管病报告 2007

5. Stroke and CHD Mortality Rate in Each Decade of Age versus Usual Systolic Blood Pressure at the Start of That Decade Age at risk (y): Age at risk (y): Stroke CHD 256 80-89 80-89 • 256 • • • • • • 128 • 70-79 • • 70-79 • • • 128 • • • • • • • • • 64 • • • • • 60-69 • 60-69 64 • • • • • • • 32 • 50-59 • 50-59 • 32 • • • • • • • • • • • • 16 • • Stroke mortality (floating absolute risk and 95% CI) • • 16 40-49 • • • • • • • • • 8 • 8 • • • • • • • • • • • 4 4 • • • • • • 2 • 2 • • • • 1 1 • • 120 140 160 180 120 140 160 180 Usual SBP (mmHg) Usual SBP (mmHg) Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

6. IDH, SDH and ISH Subtypes in American Patients 17% 16% 16% 20% 20% 11% 100% 80% 60% Frequency of hypertension subtypes in all untreated subjects (%) 40% 20% 0% <40 40-49 50-59 60-69 70-79 80+ Age (y) Frequency distribution of untreated hypertensive individuals by age and hypertension subtype. Numbers at the tops of bars represent the overall percentage distribution of untreated hypertension in that age group. ■, ISH (SBP≥140 mm Hg and DBP<90 mm Hg); ■, SDH (SBP≥140 mm Hg and DBP≥90 mm Hg); ■, IDH (SBP<140 mm Hg and DBP≥90 mm Hg). Franklin SS. Hypertension 2001;37:869

7. IDH, SDH and ISH Subtypes in Chinese Patients Huang J, et al. J Hypertens 2004;17:955-962

8. 中国高血压防治指南(2005) 心血管危险水平分层 血压(mmHg) 1级 2级 3级 SBP 140~159或SBP 160~179或SBP≥180或 DBP 90~99 DBP 100~109 DBP≥110 I 无其它危险因素 低危 中危 高危 II 1~2个危险因素 中危 中危 很高危 III ≥3个危险因素 高危 高危 很高危 或靶器官损害或糖尿病 IV 并存临床情况 很高危 很高危 很高危 其它危险因素和病史

9. 6 5.3 (2.2-13.0) 5 3.3 (1.6-6.9) 4 Relative risk of IHD 2.2 (1.3-3.7) 3 2 2.5 (1.2-5.3) Microalbuminuria 1.5 (0.9-2.7) 1 1.0 Normoalbuminuria 0 SBP < 140 SBP 140-160 SBP >160 收缩压、微量蛋白尿与心血管危险 Borch-Johnsen K, et al. Arteioscler Thromb Vasc Biol 1999; 19:1992

10. HOT：心血管危险分层与CVD事件 RR： 1.58 1.38 1.60 1.79 1.51 Cl: 1.45-1.72 1.18-1.61 1.41-1.82 1.56-2.05 1.38-1.66 P: <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 20 15 Risk: Medium Events per 1000 patient years 10 High Very High 5 0 Major cardiovascular events All myocardial infarction All stroke Cardiovascular mortality Total mortality BMJ 2002, 324:71

11. ★ ★ ★ 中国高血压防治疗指南(2010)心血管高危患者建议 • 收缩压≥180mmHg 和/或 舒张压≥110mmHg • 糖尿病 • ≥3 个心血管危险因素 • 伴1个或多个亚临床器官损害: • 心电图(尤其是心肌劳损)或超声心动图(尤其是向心性)左心室肥厚 • 超声检查显示颈动脉壁增厚或斑块 • 动脉硬度增加 • 血清肌酐轻度升高 • 估测的肾小球滤过率或肌酐清除率下降 • 微量白蛋白尿或蛋白尿 • 临床心、脑血管病或慢性肾脏疾病

12. 中国高血压防治指南(2005) 降压治疗的实施过程 • 对高血压患者临床评价后，进行心血管危险水平 分层(低危、中危、高危、很高危) • 所有患者都应采用非药物治疗措施 • 制定降压治疗计划，确定血压控制目标值 • 很高危、高危患者：立即开始药物治疗 • 中危：随访观测数周，然后决定是否开始药物治疗 • 低危：随访观测数月，然后决定是否开始药物治疗 • 治疗随访，调整治疗方案

13. Relative risk estimates of CHD events and stroke in clinical trials and in epidemiological cohort studies Meta-analysis of 147 randomised trials CHD eventsStrokes No of No of Relative risk relative risk No of No of Relative risk Relative risk Blood pressure difference trials trials events (95% CI) (95% CI) trials events (95% CI) (95% CI) No history of vascular disease 26 3429 0.79 (0.72 to 0.86) 25 2843 0.54 (0.45 to 0.65) History of coronary heart disease 37 5815 0.76 (0.68 to 0.86) 12 984 0.65 (0.53 to 0.80) History of stroke 13 567 0.79 (0.62 to 1.00) 13 1593 0.66 (0.56 to 0.79) All trials 71 9811 0.78 (0.73 to 0.83) 45 5420 0.59 (0.52 to 0.67) Cohort studies 61 10450 0.75 (0.73 to 0.77) 61 2939 0.64 (0.62 to 0.66) 0.5 0.7 1 1.4 2 0.5 0.5 0.7 0.7 1 1 1.4 1.4 2 2 Treatment better Treatment better Placebo better Placebo better For reduction of 10mmHg SBP and/or 5mmHg DBP Law MR, et al. Online from BMJ.com on 24 May, 2009

14. 在中国大陆的降压治疗临床试验 StrokeCVD STONE ↓57% ↓41% CNIT ↓50% ↓44% Syst-China ↓38% ↓37% FEVER ↓28% ↓28%

15. TEST 10 IDNT 8 PART2 RENAAL Syst-China 6 SHEP HOPE EWPHE 4 PROGESS EUROPA QUIET CHD events saved (per 1000patient-years of treatment) PEACE PATS Syst-Eur DIABHYCAR 2 MRC-E STOP-1 HDFP 0 ANBP-1 MRC-1 Coope & Warrender SCOPE -2 Dutch TIA -4 20 25 35 40 0 5 10 15 30 Absolute risk of CHD event (per 1000 patients of follow-up) 心血管危险程度与降压治疗绝对获益 CHD Events

16. 心血管危险程度与降压治疗绝对获益 STROKE 14 STOP-1 12 HSCSG PATS 10 STONE PROGESS Coope & Warrender 8 Strokes saved (per 1000patient-years of treatment) Syst-EUR 6 Syst-China SHEP EWPHE 4 HDFP MRC-E 2 MRC-1 0 0 10 20 30 40 50 60 70 Absolute risk of stroke (per 1000 patients of follow-up)

17. BP-Lowering Treatment TrialistsComparisons of Different Active Treatments BP Difference(mm Hg) Relative Risk RR (95% CI) Major CV events ACEI vs D/BB 2/0 1.02 (0.98, 1.07) CA vs D/BB 1/0 1.04 (0.99, 1.08) ACEI vs CA 1/1 0.97 (0.92, 1.03) CV mortality ACEI vs D/BB 1.03 (0.95, 1.11) 2/0 CA vs D/BB 1.05 (0.97, 1.13) 1/0 ACEI vs CA 1.03 (0.94, 1.13) 1/1 Total mortality ACEI vs D/BB 1.00 (0.95, 1.05) 2/0 CA vs D/BB 0.99 (0.95, 1.04) 1/0 ACEI vs CA 1/1 1.04 (0.98, 1.10) FavorsFirst Listed FavorsSecond Listed 0.5 1.0 2.0 Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

18. BPLTT: STROKEComparisons of different active treatments2003 BP difference (mm Hg) Favours second listed Favours first listed RR (95% CI) 2/0 ACEI vs. D/BB 1.09 (1.00,1.18) 1/0 CA vs. D/BB 0.93 (0.86,1.01) 1/1 ACEI vs. CA 1.12 (1.01,1.25) 0.5 1.0 2.0 Relative Risk

19. Coronary heart disease events Stroke • No of No of Relative risk relative risk No of No of Relative risk Relative risk • trials events (95% CI) (95% CI) trials events (95% CI) (95% CI) • Thiazides 11 1710 0.86 (0.75 to 0.98) 10 1370 0.62 (0.53 to 0.72) • blockers 6 851 0.89 (0.78 to 1.02) 7 690 0.83 (0.70 to 0.99) Anglotensin converting enzyme inhibitors 21 4083 0.83 (0.78 to 0.89) 13 1220 0.78 (0.66 to 0.92) Angiotensin receptor blockers 4 378 0.86 (0.53 to 1.40) 0 0 Calcium channel blockers 22 2009 0.85 (0..78 to 0.92) 9 976 0.66 (0.58 to 0.75) Drug choice open 5 871 0.89 (0.78 to 1.01) 4 763 0.96 (0.75 to 1.23) All classes of drug 64 9417 0.85 (0.81 to 0.89) 38 4712 0.73 (0.66 to 0.80) 2 1.4 0.5 0.7 1 1.4 2 0.5 0.7 1 Specified Drug better Specified Drug better Placebo better Placebo better Relative risk estimates of CHD events and stroke according to class of drug Excluding CHD events in trials of β blockers in people with a history of CHD Law MR, et al. Online from BMJ.com on 24 May, 2009

20. BPLTTC (WHO/ISH, 2003) 1.50 1.50 1.50 Stroke Major CVD CHD 1.25 1.25 1.25 1.00 1.00 1.00 0.75 0.75 0.75 0.50 0.50 0.50 0.25 0.25 0.25 -10 -8 -6 -4 -2 0 2 4 -10 -8 -6 -4 -2 0 2 4 -10 -8 -6 -4 -2 0 2 4 1.50 1.50 CVD death Total mortality 1.25 1.25 1.00 1.00 0.75 0.75 0.50 0.50 0.25 0.25 -10 -8 -6 -4 -2 0 2 4 -10 -8 -6 -4 -2 0 2 4 Relative risk of outcome event SBP difference between randomized groups (mmHg) Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

21. 中国高血压防治指南(2005) 血压控制目标值 • 中青年高血压患者 <140/90 mmHg • 老年高血压患者 <150/90 mmHg • 糖尿病或肾病患者 <130/80 mmHg

22. INVEST 血压控制达标与终点事件发生的关系 15.0 一级终点 心肌梗死（致死＋非致死性） 脑卒中（致死＋非致死性） 16 14 12 10 8 6 4 2 0 P值均小于0.001 发生临床终点事件百分比 10.8 9.2 8.1 5.7 4.3 3.8 3.1 2.3 2.4 1.6 1.1 <25% ≥25%至<50% ≥50%至<75% ≥75% 随诊时血压达标百分比（140/90 mmHg） 患者总数（n） 3838 3757 6664 8316

23. Clinical outcomes by proportion of time with BP Control (covariate adjusted) proportion of time with BP HR (95% CI) Reduced Risk Increased Risk Control (< 140; 90mmHg) Primary Endpoint < 25% 1.79 (1.357-2.363) ≥ 25% to < 50% 1.30 (1.035-1.625) ≥ 50% to < 75% 1.06 (0.875-1.277) ≥ 75% 1.00 CV morbidity or Mortality < 25% 1.76 (1.382-2.243) ≥ 25% to < 50% 1.24 (1.009-1.513) ≥ 50% to < 75% 1.14 (0.893-1.250) ≥ 75% 1.00 MI (Fatal and non fatal) < 25% 1.64 (1.073-2.509) ≥ 25% to < 50% 1.24 (0.079-1.757) ≥ 50% to < 75% 1.14 (0.859-1.512) ≥ 75% 1.00 Stroke (Fatal and non fatal) < 25% 2.04 (1.270-3.265) ≥ 25% to < 50% 1.14 (0.761-1.697) ≥ 50% to < 75% 1.11 (0.822-1.535) ≥ 75% 1.00 Hospitalization for CHF < 25% 1.74 (1.157-2.630) ≥ 25% to < 50% 1.16 (0.831-1.630) ≥ 50% to < 75% 0.99 (0.746-1.314) ≥ 75% 1.00 0 0.5 1 1.5 2 2.5 3 3.5 HR (95% CL) Exponential time-to-event model adjusted for covariates age. BMI history of CHD. Stroke. LVH. Type 2 diabetes. Smoking. High total cholesterol and proteinuria. Additional adjustment for 5th order polynomials of msDBP and msSBP. VALUE：BP Control and Outcomes

24. 30 Hypertensive with diabetes (n=1501) All hypertensive patients (n=18790) 25 P=0.005 for trend 20 Major cardiovascular events/ 1000 patients-years 15 P=0.50 for trend 10 5 0  80  85  90  80  85  90 Target blood pressure groups HOT: 糖尿病患者血压控制与CV事件发生率 Major cardiovascular events (per 100 patients-years) in all treated hypertensive and in hypertensive patients with diabetes in relation to target blood pressures of 90. 85, and 80 mm Hg.

25. 10 9 8 7 Annual patient event rate (%) 6 5 4 100 110 120 130 140 150 160 170 Achieved systolic blood pressure (mmHg) Median systolic blood Pressure (mmHg) 106 116 125 135 144 154 168 No. of person- Years 1431 4266 8974 11983 9138 4942 3470 ADVANCE: Achieved BP levels and all renal events De Galan BE, et al. J Am Soc Nephrol. 2009; Feb.18, online

26. SBPs achieved by treatment in placebo-controlled trials in elderly hypertensives Achieved SBP N Age(years) Baseline SBP Active Control EWPHE 840 72 182 150 172 Coope and Warrender 884 68 196 162 180 SHEP 4376 72 170 143 155 STOP-1 1627 76 195 167 186 MRC elderly 4396 70 185 156 165 Syst-Eur 4695 70 174 151 161 Syst-China 2394 67 171 151 160 SCOPE 4964 76 166 145 148 HYVET 3845 83 173 144 159 JATOS 4418 74 171 138 147 Zanchetti A, et al. J Hypertens. 2009;27:

27. 中国高血压防治指南(2005) 长期治疗随访实施过程 治疗3个月后， 达到降压目标值 治疗3个月后，未 达到降压目标值 有明显副作用 • 继续治疗 • 血压控制1年以上 可减少剂量 • 增加剂量 • 改用另一类降压药 • 联合治疗 • 改用另一类降压药 • 减少剂量

28. ◆ 降压治疗后血压下降幅度主要取决于： 血压水平和药物平均剂量 SBP↓= 9.1+0.1(P-154) DBP↓= 5.5+0.11(P-97) Law MR, et al. BMJ. 2003;326:1427-1431.

29. 降压药物联合治疗的依据(一) ◆ 150/90时，一种药物在标准剂量下，血压平均 降低仅8.7/4.7 mmHg；一种、两种、三种药物 在1/2标准剂量下，血压分别平均降低6.7/3.7、 13.3/7.3、19.9/10.7 mmHg。 SBP↓= R+n×0.078 (P-150) DBP↓= R+n×0.088 (P-90) Law MR, et al. BMJ. 2003;326:1427-1431.

30. Doubling dose of same drug (from standard dose to twice standard) Adding a drug from another class (on average standard doses) 1.16 (0.93-1.39) 1.4 1.00 (0.76-1.24) 1.04 (0.88-1.20) 1.01 (0.90-1.12) 0.89 (0.69-1.09) 1.2 1.0 0.8 Incremental systolic blood pressure reduction Ratio of observed to expected additive effects 0.6 0.37 (0.29-0.45) 0.23 (0.12-0.34) 0.19 (0.08-0.30) 0.4 0.2 (0.14-0.28) 0.22 (0.19-0.25) 0.2 0 Calcium channel blocker Thiazide Beta blocker All Classes ACE Inhibitor 降压药物联合治疗的依据(二) Combination Therapy Versus Monotherapy Meta-analysis from 42 trials Wald DS, et al. Am J Med. 2009;122:290-300.

31. 降压药物联合治疗的依据(三) • 通过不同的药理作用，中和或对抗相互的不良反应。 • 通过降低剂量减少和减轻不良反应。 不良反应(A+B) < 不良反应(A) + 不良反应(B) 不良反应(A+B) < 不良反应(2A) 或 < 不良反应(2B)

32. 优化降压联合治疗方案 DHP-CCB + ACEI/ARB ★ ★ ★ (ASCOT, ACCOMPLISH) DHP-CCB + βblocker ★ ★ (HOT, INSIGHT, ALLHAT) ACEI/ARB + Diuretics★ ★ (LIFE, VALUE, ACCOMPLISH) DHP-CCB + Diuretics★ ★ (VALUE, FEVER) ACEI/ARB + β blocker★ (ALLHAT) β blocker + Diuretics ★ (LIFE, ASCOT, INSIGHT) ACEI + ARB ─ (ONTARGET)

33. INSIGHT：糖尿病患者终点事件 所有主要终点,非心脑血管性死亡,ESRD,心绞痛和短暂性脑缺血 Co-amilozide Nifedipine GITS 20.0 18.7 p = 0.03 16.0 14.2 12.0 患者百分数(%) 8.0 4.0 0.0 Nifedipine GITS Co-amilozide Mancia G, et al. Hypertension 2003;41:431–6.

34. INSIGHT serious and metabolicadverse events Serious adverse events p=0.02 0% 5% 10% 15% 20% 25% 30% Hypokalaemia p<0.0001 Hyponatraemia p<0.0001 Hyperlipidaemia p<0.0001 Hyperglycaemia p=0.001 Nifedipine GITS Co-amilozide Hyperuricaemia p<0.0001 Impaired renal function p<0.0001 0% 2% 4% 6% 8% 10% Brown M, et al. Lancet 2000;356:366–72.

35. INSIGHT:对新发糖尿病的影响 176 (5.6%) 180 p=0.023 160 136 (4.3%) 140 120 Patients with newly diagnosed diabetes mellitus (n) 100 80 60 40 20 0 Nifedipine GITS Co-amilozide Mancia G, et al. Hypertension 2003;41:431–6.

36. ASCOT-BPLA:终点事件发生率 （氨氯地平+/-培哚普利 Vs. 阿替洛尔+/-苄氟噻嗪） 总心血管 事件和 介入 致死/ 非致死性 卒中 心血管 死亡 非致死心梗 和冠心病死亡 新发 糖尿病 总死亡 总冠脉事件 肾损害 0 -5 降低百分比 (%) -10 * -15 * * * -20 -25 * * -30 * *P<0.05 -35 Dahlof B, Sever P, et al. Lancet. 2005;366:895-906.

37. 20% Risk Reduction ACCOMPLISH: 主要终点 ACEI / HCTZ 650 CCB / ACEI 526 HR (95% CI) 0.80 (0.72, 0.90) Cumulative event rate p = 0 .0 0 0 2 Time to 1st CV morbidity/mortality (days)

38. 中国高血压人群的临床特点 • 最主要的心血管危险是脑卒中 • 高血压发生和血压水平与摄盐量或饮食钠/钾比值较高密切有关 • 老年人占的比例很高 • 约定1/10男性患者有嗜酒行为

39. 脑卒中与心肌梗死的比值 不同临床试验比较 STONE 8.0 Syst-China 8.7 NICS-EH 4.0 SHEP 1.2 MRC II 0.8 STOP-H 1.2 Syst-Eur 1.7

40. Primary Endpoint – Efficacy Primary Endpoint – safety Any CV Event Death, any CV Event or Revascularisation Any Vascular Event or Revascularisation All patients ISH patients Hypertensives Favours Nifedipine GITS Favours Placebo 0.65 1 1.3 HR (95% CI) Elliott & Meredith, 2009 ACTION: Events in Patients with Hypertension vs ISH

41. Initial therapy with a low dose DHP-CCB or DHP-CCB/RAS blocker or DHP-CCB/β-blocker combination IS BLOOD PRESSURE CONTROLLED ? Yes No Up-titration of combination therapy successively to the highest dose Continue with current therapy Yes No DHP-CCB/RAS blocker/diuretic or DHP-CCB/β-blocker/diuretic combination and up-titration Continue with Current therapy Continue with current therapy Yes No Continue with current therapy Add an a-blocker, Or spironolactone 降压治疗方案推荐流程

42. 欧洲高血压治疗指南修改背景 (ESC/ESH,2009) Different interpretations of results/potential for confusing messages to clinical practice Reinforcement of previous recommendation New recommendation

43. 欧洲高血压治疗指南修改要点 (ESC/ESH,2009) ◆ 重申心血管危险分层 ◆推荐80岁以上高龄高血压患者实施降压治疗 ◆ 解释启动降压治疗血压水平和血压控制目标 一般人群：≥ 140/90，<140/90 高危以上人群：< 130/85，<130/80 ◆ 建议在心血管高危患者血压控制不低于120/70。 ◆ 淡化一线降压药物概念，强调首选联合治疗， 重视ACEI、ARB和CCB的治疗地位。