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1、高血压治疗 新的循证医学证据,华中科技大学协和医院心内科 廖玉华,高血压治疗：新的循证医学证据,ADVANCE研究 固定复方制剂 VALIDD研究 降压与心室舒张功能 A meta-analysis of RCTs 中国人高血压临床试验证据,ADVANCE研究: 在11,140例2型糖尿病患者中进行的降压与强化血糖控制的析因随机临床试验,培哚普利吲达帕胺固定复方制剂（百普乐）对重要血管事件的影响,Inclusion criteria,Type 2 diabetes mellitus Age 55 years or older Additional risk of vascular event
2、Age 65 years History of major macrovascular disease History of major microvascular disease First diagnosis of diabetes 10 years prior to entry Other major risk factor Hypertensive or normotensive,Randomised study treatments,Blood pressure lowering Double-blind perindopril-indapamide versus matching
3、placebo 2.0 / 0.625mg or placebo for first 3 months 4.0 / 1.25mg or placebo thereafter Blood glucose lowering (ongoing) Open-label gliclazide MR-based intensive therapy targeting an HbA1c of 6.5% versus usual guideline-based care,Among patients with diabetes, does blood pressure lowering therapy: Pr
4、oduce additional benefits when systolic pressure is lowered below 145 mmHg? Produce similar benefits for hypertensive and non-hypertensive patients? Add to the benefits produced by other cardiovascular preventive therapies including ACE inhibitors?,ADVANCE study hypotheses Perindopril-indapamide arm
5、,ADVANCE Trial profile,12877 with type 2 diabetes registered,11140 randomised,5569 assigned perindopril-indapamide combination,1737 withdrew during run-in,Scheduled end of follow-up: 4.3 years 4908 (88%) assessed at final visit 4081 (73%) adherent to treatment,4 lost to follow-up,11 lost to follow-u
6、p,Scheduled end of follow-up: 4.3 years 4863 (87%) assessed at final visit 4143 (74%) adherent to treatment,5571 assigned matching placebo,血压降低情况, 2.2 mmHg (95% CI 2.0-2.4); p0.001, 5.6 mmHg (95% CI 5.2-6.0); p0.001,Diastolic,Systolic,安慰剂组,培哚普利/吲达帕胺组,Mean Blood Pressure (mmHg),65,75,85,95,105,115,12
7、5,135,145,155,165,Follow-up (Months),R,6,12,18,24,30,36,42,48,54,60,全因死亡率,Follow-up (months),0,10,0,6,12,18,24,30,36,42,48,54,60,Cumulative incidence (%),Relative risk reduction 14%: 95% CI 2-25% p=0.025,5,死亡分析,心血管死亡,Follow-up (months),6,12,18,24,30,36,42,48,54,60,安慰剂组,培哚普利/吲达帕胺组,非心血管死亡,Follow-up (m
8、onths),6,12,18,24,30,36,42,48,54,60,安慰剂组,培哚普利/吲达帕胺组,相对危险降低 18%; p=0.027,相对危险降低 8%; p=0.41,5%,5%,Cumulative incidence (%),Coronary events,*2P=0.02,Non-fatal MI or death from coronary heart disease Unstable angina requiring hospitalisation, coronary revascularisation or silent MI,Major coronary heart
9、disease,265,294,11% (-6 to 24),All coronary heart disease,468,535,14% (2 to 24),Other coronary heart disease,283,324,14% (-1 to 27),*,Number of events,Per-Ind,Placebo,(n=5,569),(n=5,571),Relative risk,reduction (95% CI),Favours,Per-Ind,Favours,Placebo,Hazard ratio,0.5,1.0,2.0,Cerebrovascular events,
10、Major cerebrovascular disease,215,218,2% (-18 to 19),All cerebrovascular disease,286,303,6% (-10 to 20),Other cerebrovascular disease,79,99,21% (-6 to 41),2.0,*,*2P=0.40,Non-fatal stroke or death from cerebrovascular disease Transient ischaemic attack or subarachnoid haemorrhage,Number of events,Per
11、-Ind,Placebo,(n=5,569),(n=5,571),Relative risk,reduction (95% CI),Favours,Per-Ind,Favours,Placebo,Hazard ratio,0.5,1.0,Renal events,2.0,Hazard ratio,0.5,1.0,New or worsening nephropathy,181,216,18% (-1 to 32),New microalbuminuria,1094,1317,21% (14 to 27),Total renal events,1243,1500,21% (15 to 27)*,
12、*2P=0.01,Number of events,Per-Ind,Placebo,(n=5,569),(n=5,571),Relative risk,reduction (95% CI),Favours,Per-Ind,Favours,Placebo,*多为新发微量白蛋白尿,常规使用培哚普利与吲达帕胺的绝对获益,总结,2型糖尿病患者常规使用培哚普利/吲达帕胺治疗的结果: 总死亡率降低14% 心血管死亡降低18% 主要血管事件降低9% 总冠脉事件降低14% 总肾脏事件降低21%,这些获益在所有主要亚组都相似。治疗的耐受性非常好，副作用很少，遵从治疗的情况与安慰剂组相似。,Among patie
13、nts with diabetes, does blood pressure lowering therapy: Produce additional benefits when systolic pressure is lowered below 145 mmHg? Produce similar benefits for hypertensive and non-hypertensive patients? Add to the benefits produced by other cardiovascular preventive therapies including ACE inhi
14、bitors?,Blood pressure lowering in diabetes: Unresolved issues 2000,YES,YES,YES,VALIDD研究,The Influence of Angiotensin Receptor Blockers and Blood Pressure Lowering on Diastolic Function in Patients with Hypertension and Diastolic Dysfunction: The VALsartan In Diastolic Dysfunction 血管紧张素受体拮抗剂(ARB)对高血
15、压和舒张功能不全患者的作用,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,研究目的,目的:验证下列假说是否正确 “ARB较其他非阻断RAAS系统的降压药物更有效改善左室舒张功能”,？,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,研究设计,482例初选患者 年龄大于45岁、1、2级高血压、无心功能不全病史,组织多普勒检查，评价心肌舒张速度，确定舒张功能不
16、全的存在,384例舒张功能不全的患者,缬沙坦组(n=186) 320mg/d,非RAAS拮抗剂降压治疗(n=198) 钙拮抗剂、利尿剂、阻滞剂,随机分组,观察终点,38周前后的舒张速度、等容舒张时间（S)、加速时间、E/A、E/E 左室容积质量、射血分数,随访38周,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,ARB vs. 非RAAS阻断剂组:降压幅度相当,38周后,两组的血压较基线相比降低幅度没有显著差异,收缩压较基线的改变(mmHg),缬沙坦组(n=186),非RA
17、AS阻断剂组(n=198),p = NS,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,ARB vs. 非RAAS阻断剂组:改善舒张功能疗效相当,38周后,ARB和非RAAS阻断类降压药物均显著改善舒张功能，疗效相当,*每组治疗前后比较P0.0001, *组间比较P=NS,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,研究结论,轻中度高血压患者虽然左室肥
18、厚发生率低，但已经存在心肌舒张功能不全，这是高血压靶器官受累的早期标志，进而将导致左室肥厚,在降压疗效相同时，ARB和非RAAS阻断类降压药物均显著改善心肌舒张功能，疗效相同,降压治疗带来又一项收益，即改善舒张功能。即便是轻中度高血压患者，也可受益,Solomon S. American College of Cardiology 2007 Scientific Sessions, March 25, 2007.,VALIDD评论,50%高血压患者存在舒张功能不全，虽然部分患者最终进展为心衰，但是迄今仍然没有具备针对性的治疗方法。 VALIDD研究证实降低血压可有效改善舒张功能不全，即使轻中度
19、高血压患者也可获益。 这一结果说明：对于高血压患者，应该采取积极降压措施 Dr Scott Solomon，VALIDD研究领导人，布莱根女子医院，哈佛医学院,Prevention of stroke and MI by amlodipine and ARBs 氨氯地平与ARBs预防卒中与心肌梗死 A meta-analysis of RCTs 随机对照临床试验综合分析,Wang JG et al. Hypertension 2007; 50: 333-339.,氨氯地平 vs. ARBs*: 脑卒中,氨氯地平较好,ARBs较好,IDNT VALUE CASE-J 所有试验 p = 0.46,
20、30/579 322/7649 60/2354 412/10,582,18/567 281/7596 47/2349 346/10,512,15.9% (6.2) 2p = 0.02,0.5,1.0,1.5,2.0,* 厄贝沙坦、缬沙坦、坎地沙坦,ARBs,氨氯地平,试验,事件数 / 研究对象人数,异质性检验,危险比 (95%可信区间),差别 (SD),Wang JG et al. Hypertension 2007; 50:333-339.,IDNT VALUE CASE-J All trials p = 0.40,51/579 369/7649 17/2354 437/10,582,33/
21、567 281/7596 18/2349 332/10,512,16.7% (6.1) 2p = 0.01,0.5,1.0,1.5,2.0,氨氯地平 vs. ARBs*: MI,ARBs,试验,事件数 / 研究对象人数,异质性检验,危险比 (95%可信区间),差别 (SD),氨氯地平,氨氯地平较好,ARBs较好,* 厄贝沙坦、缬沙坦、坎地沙坦,Wang JG et al. Hypertension 2007; 50:333-339.,SCOPE n=4937,Difference (reference minus experimental) in SBP (mmHg),脑卒中,Odds rat
22、io (experimental/reference),Placebo n=3279,ASCOT n=19,257,ACEIs n=19,438,ARBs n=21,094,ALLHAT/Diu n=24,303,LIFE n=9193,Ena/Nit n=1602,Amlodipine n=21,094,Placebo n=2661,Wang JG et al. Hypertension 2007; 50: 333-339.,SCOPE n=4937,Difference (reference minus experimental) in SBP (mmHg),心肌梗死,Odds ratio
23、 (experimental/reference),Placebo n=3279,ASCOT n=19,257,ACEIs n=19,438,ARBs n=21,094,ALLHAT/Diu n=24,303,LIFE n=9193,Ena/Nit n=1602,Amlodipine n=21,094,Placebo n=2661,Wang JG et al. Hypertension 2007; 50: 333-339.,Improve BP lowering, improve outcome 提高降压质量，改善结局,FEVER: 研究设计和治疗流程图,1344 Z,+ 非洛地平 5 mg/
24、d,+ 安慰剂,HCTZ 12.5 mg/d,随访 周,1 -6,2 -4,3 -2,4 0,5 1,6 2,7 3,8 4,9 5,10 6,11 9,12 12,16 24,20 36,24 48,28 60,月,筛选,随机化,如果BP 160/90 mmHg ，研究人员可根据判断加用利尿剂或其他药物（不包括钙离子拮抗剂）,FEVER：SBP变化,1351 Z,SBP (mmHg),随访 (月),142.5,137.3,141.6,138.1,安慰剂 非洛地平,S,R,FEVER：DBP变化,1352 Z,DBP (mmHg),随访 (月),85.0,82.5,83.9,82.3,安慰剂
25、非洛地平,S,R,脑卒中(致死性和非致死性)的Kaplan-Meier曲线,1356 Z,随访 (月),HR = 0.732, 95% CI: 0.601-0.891, p = 0.0019,事件患者比例 (%),0,6,12,18,24,30,36,42,48,54,60,0,2,4,6,8,10,-26.8%,0,6,12,18,24,30,36,42,48,54,60,0,3,6,9,12,15,所有心血管事件的Kaplan-Meier曲线,1356 Z,随访 (月),HR = 0.726, 95% CI: 0.612-0.860, p = 0.0002,安慰剂 非洛地平,事件患者比例
26、(%),-27.4%,从2007ESH/ESC高血压治疗指南看 FEVER研究的价值,Journal of Hypertension 2007, 25:11051187,FEVER研究是首个被ESH/ESC指南推举的中国临床研究 在FEVER研究中，中危高血压患者在基础治疗（ HCTZ12.5 mg/d ）血压控制在160/90mmHg以下时，非洛地平与安慰剂组相比，血压轻度下降(-3.5/-1.5mmHg)，总的心血管终点事件发生率显著降低达28% FEVER研究结果表明，即使在中度危险的高血压患者，与SBP降至轻微140mmHg相比，SBP降至140mmHg的保护作用更明显，这个发现支持当收缩压为140mmHg时即考虑开始抗高血压治疗的建议,2007 ESH/ESC高血压治疗指南新特点,高血压的定义和分类： 诊断高血压和指导治疗要求正确的血压测量，并对总的心血管危险作评价 强调血压降低的重要性以保护高血压患者 治疗： 对每一个人都要建议生活方式的改变 不同的药物种类均可作为初始和维持降压治疗 联合治疗也应考虑为一很好的首选治疗,2007 ESH-ESC 高血压指南,器官损害的识别: 应在整个治疗过程中对器官损害进行评估 器官损害评估新增加： 微量白蛋白尿或蛋白尿 肾小球滤过率或肌酐清除率 踝-臂指数 脉搏波速率,