高血压的联合用药新进展

高血压的联合用药新进展 首都医科大学宣武医院 华 琦 高 血 压 ★引发多种疾病 心肌梗死（MI） 脑血管疾病（CVA） 外周血管疾病（PVD） 充血性心衰（CHF） 肾功能衰竭（Renal failure） 高血压控制率（％） 加拿大 16.0 USA 27.4 苏格兰 17.5 英格兰 9.0 法国 27.0 西班牙 15.5 萨伊 2.5 意大利 23.4 印度 9.0 澳大利亚 7.0 德国 22.5 芬兰 20.5 JNC - VI Arch Intern Med . 1997;157 ： 2413 - 2446. Burt et al. Hypertension. 1995;26:60 - 69. Mancia G et al. Eur Heart J . 1999;( suppl L):L14 - L19. Pnmatesta P et al. Hypertension .2001;38:827 - 832 中国 6% 中国居民营养与健康现状调查--中华人民共和国卫生部、中华人民共和国科学技术部、中华人民共和国国家统计局；2004年10月12日 世界各国高血压控制率均不乐观 显而易见，尽管现有大量抗高血压药物， 治疗现状仍不容乐观（ESH）1 ★全球有6亿人口受到高血压的侵害（WHO）2   ★我国最新调查显示高血压患者1.6亿，知晓率30.2%，治疗率为24.7%，控制率仅为6％，94％的患者未得到控制（国家卫生部）3 1.  Executive Summary. The 14th meeting of the European Society of Hypertension ( ESH ), June 14, 2004, Pairs, France 2.   Cardiovascular Diseases-Prevention and Control, WHO, 2001-2003 3. 中国居民营养与健康现状调查，中华人民共和国卫生部，中华人民共和国科学技术部，中华人民共和国国家统计局，2004年10月12日 ESH - ESC Guidelines, J Hypertens 2003 -控制血压 所有高血压病人:BP < 140/90 mmHg 伴有糖尿病或肾病的高血压病人: BP< 130/80 mmHg -控制全部心血管危险因素 治疗目标 药物联合治疗 药理学原则 治疗作用 协同(Synergism) 1+1>2 相加(Addition) 1+1=2 不良作用 抵消 相减 降压药单药治疗的控制率 达到 BP:<140/90 mmHg Dickerson et al, Lancet, 1999 单药治疗 (利尿药, b-阻滞剂, ACEI或钙拮抗剂) % 39 0 20 40 60 80 Methods：56 patients, mean blood pressure 161/98 mm Hg,entered the rotation, of whom 36 received all four monthly cycles of treatment with an angiotensin-converting-enzyme (ACE) inhibitor (A), _-blocker (B), calcium-channel blocker (C), and diuretic (D). Each patient’s best drug was then repeated to assess repeatability. Two measures of individual variability in response were used. First, the value of rotation was measured by the ncreased proportion of patients reaching target blood pressure on their best drug versus their first drug. Second, we assessed whether the responses to each drug were correlated with each other. Findings： Significant variability in response was found. 20 of the 41 patients reaching target blood pressure (_140/90mm Hg) failed to achieve this target on their first drug. Rotation increased from 22/56 (39%) to 41/56 (73%) the success of monotherapy (p=0·0001); in half the patients, blood-pressure on the best treatment was 135/85 mm Hg or less. There were significant correlations between the blood pressure responses to A and B (r=0·5, p<0·01), and C and D (r=0·6, p<0·001), but not between the other four pairings of treatments. The responses to the AB pair were, on average, at least 50% higher than those to the CD pair;this difference was highly significant by multivariate in individual responses to the different agents. A few investigators have observed such variability during crossover studies,2–7 and systematic rotation through each class has been suggested as the most logical, if laborious, approach to treatment.8,9 However, to our knowledge no prospective rotation study of the four main classes of antihypertensive drugs has previously been done. 联合治疗的合理性 -药物联合通过不同的机制降压  降压疗效  -不同类药物的副作用可能相互抵消 -不同峰效应时间的药物联合有可能延长降压作用时间 -联合用药一般只需小剂量 不良反应发生  药物联合治疗的降压疗效约为两个组成单药疗效之和，但副作用少于两个单药副作用之和 M R Law,N J Wald, et al. BMJ 2003, 326: 1427 对354个随机双盲安慰剂对照试验的荟萃 分析 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 单药与联合治疗降压疗效比较 -7 -8.1 -14.6 -4.1 -4.6 -8.6 -16 -14 -12 -10 -8 -6 -4 -2 0 收缩压 舒张压 单用“第一种药” 单用“第二种药” 联合用药 减去安慰剂作用后的 血压反应 mmHg BMJ  2003;326:1427 (28 June), doi:10.1136/bmj.326.7404.1427 Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials M R Law, professor1, N J Wald, professor1, J K Morris, senior lecturer1, R E Jordan, research assistant1 Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. Subjects 40 000 treated patients and 16 000 patients given placebo. Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69. 维持血压的主要机制 “DASH”-- 联合用药的背景 降压药物的联合应用 D Direct (Autoregulation) A Adrenergic mechanisms S Salt (sodium chloride) H Humors/hormones(AII,NE,ET) 联合用药的优势 协同降压； 兼顾并存疾病； 减少不良反馈； 减少大剂量引起的副作用； 增加患者依从性。 联合用药的适应状况 一种药物达充量而血压不能控制时； 患者血压高于目标血压20/10mmHg； 患者并存多种危险因素或疾病； 应注意体位低血压，尤其糖尿病、老年及植物神经障碍； 注意药物价格，以保证患者有足够的费用长期甚至终身服药。 六大类降压药的相同与不同 相同之处 降压幅度相同 不同之处 强适应症不同 对靶器官保护作用不同 疗效与副反应的模式不同 六大类降压药中任何一类药物，起始剂量单一用药只能降低收缩压约10mmHg 六大类降压药之间在降压幅度上相同，要避免片面夸大某一类降压药物的降压作用， 10的法则（Rule of TENS） 单种抗高血压药往往不能满足多种降压机制 而增加单药剂量，虽可增加稍稍控制率，但往往使副作用大幅度升高 因此提出：小剂量联合治疗原则 抗高血压药物联合治疗的途径 处方临时联合 固定剂量联合 前面谈到抗高血压药物联合治疗是必不可少的治疗选择,下面我们将探讨处方临时联合与固定剂量联合哪一种方法更具优越性? 处方临时联合的优劣势 优势:因人而异（病情、经济）；易于调整 劣势:不合理临床联合应用、不能达到协同降压，反增加副作用.治疗 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 较复杂，病人服用不方便，降低依从性,费用较高（如：钙离子拮抗剂+ACEI） 优势: 配方合理时：降压疗效增加，更易达到靶目标值, 简化治疗,价格低廉 劣势: 处方固定，不易调整 处方固定联合的优劣势 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) 更加关注收缩压 对于> 50 岁的患者，收缩压是比舒张压更重要的心血 管疾病危险因素 55岁血压正常的人有高达90%的机会发展成为高血压 收缩压达标是治疗的首要目标 为达到目标血压，绝大部分患者需要服用二种或以上的降压药物。 若血压比目标水平 >20/10 mmHg 以上， 初始治疗即应启用两种药物的联合治疗，其中一类药物为噻嗪类利尿剂。 JNC 7(2003)高血压治疗的趋势 (读片)—再次强调收缩压控制的重要性 降压药物治疗原则 从低剂量开始治疗，逐步递增剂量 最好使用长效降压药，每日给药一次 采用两种或两种以上合理的联合治疗方案 联合用药 HOT研究证实，90%以上患者舒张压降至90mmHg以下的实验中，70%须采用联合药物治疗。联合作用相加药物使血压降低幅度大约是单一药物的2倍，即约降低8-15%。不同类药物联合使用可因药物主要作用机制不同而产生相加的降压效果，又最大程度减少限制血压降低的代偿反应；减轻可能存在的剂量相关性副作用。 需要用联合治疗来血压达标 Monotherapy Combination therapy 59% 32% SBP/DBP mm Hg 161/98 142/83 SBP/DBP mm Hg 140/81 26% 80 mm Hg 142/83 32% 85 mm Hg 144/85 37% 90 mm Hg Enrolment Final Hansson et al 1998 HOT 良好的血压控制往往需要多种抗高血压药物联合应用 平均应用抗高血压药的数量 试验 目标血压 （ mmHg ） UKPDS= 英国前瞻性糖尿病研究， ABCD ＝ 糖尿病患者合理血压控制研究， MDRD ＝ 肾病的饮食调整研究， HOT ＝ 高血压合理治疗研究， AASK ＝ 非裔美洲 肾病患者干预研究， IDNT ＝ 伊贝沙坦治疗糖尿病肾病研究 UKPDS DBP<85 ABCD DBP<75 MDRD DBP<92 HOT DBP<80 AASK MAP<92 IDNT SBP/DBP 135/85 Bakris GL et al. Am J Kidney Dis . 2000;36:646 - 661. Lewis EJ et al. N Engl Med. 2001;345:851 - 860 中国高血压防治指南推荐的 降压联合治疗方案2004 现有的临床试验结果支持以下类别降压药的组合: *         利尿药和阻滞剂 *        利尿药和ACEI或ARB *         钙拮抗剂(二氢吡啶)和阻滞剂 *        钙拮抗剂和ACEI或ARB *        钙拮抗剂和利尿药 *         阻滞剂和阻滞剂 必要时也可用其他组合，包括中枢作用药如受体激动剂、咪达唑啉受体调节剂，以及ACEI与ARB。 　 中国高血压防治指南编写专家组 欧洲高血压指南2003 利尿药 ACE抑制剂 钙拮抗剂 阻滞剂 ARB 不同降压药的可能联合,实线为最合理联合, 有外框的药物已有对照干预试验 证明 住所证明下载场所使用证明下载诊断证明下载住所证明下载爱问住所证明下载爱问 有益 阻滞剂 JNC-7 降压治疗方针 ● 噻嗪类利尿剂应被视为首选用药，可单独或与其它药物联合应用。 当SBP比目标值高20mmHg，DBP比目标值高10mmHg时，联合药物治疗应作为一线用药(通常包括利尿剂)。 JNC-7(2003) 最大作用的百分数 剂量单位 0 1 10 100 1000 10000 0 20 40 60 80 100 治疗作用 毒性作用 临界剂量 合适剂量 A basic principle of pharmacology is that drugs are following the log-linear dose-dependent curve. That means that, the higher the dose of a drug, the greater its therapeutic action and toxicity. At low doses the therapeutic effect is much higher than the toxic effect. So, application of this pharmacological principle suggests that an equally rational approach in therapy is to use a combination of low doses of two drugs with complementary mechanisms of action. Monotherapy relies on increasing the dose when the patient does not respond, thereby increasing side effects. A low-dose combination relies on combining drugs with complementary modes of action to obtain a higher responder rate and a lower rate of side effects. Because many, and probably most, side effects are dose-related, and because side effects differ between classes of antihypertensives, it follows that when an equal antihypertensive effect is obtained by the fixed low-dose combination of two drugs from two different classes, the side-effect profile is lower. And it is particularly attractive with a combination of drug classes that in themselves have an excellent tolerability profile (such as the ACE inhibitor perindopril and a diuretic without metabolic side effects such as indapamide). 有不良反应病人的百分数 标准 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 剂量 双倍标准剂量 标准剂量半量 -阻滞剂 ACEI 噻嗪类利尿药 钙拮抗剂 ARB 20 15 10 5 0 -5 临床试验数 59 96 62 96 44 M R Law，N J Wald, et al. BMJ 2003, 326: 1427 不同剂量降压药物的不良反应发生率 所有不良反应发生率都已减去安慰剂组的不良反应。 降压药物剂量越大不良反应发生率越高 小剂量联合治疗——减少不良反应 Calculated as difference between treated and placebo groups in proportion of participants who developed one or more symptoms, excluding headaches, which were significantly less common in people receiving treatment.Commonest symptoms: thiazides—dizziness, impotence, nausea, muscle cramp; β blockers—cold extremities, fatigue, nausea; ACE inhibitors—cough; calcium channel blockers—flushing, ankle oedema, dizziness.7BMJ. 2003 June 28; 326(7404): 1427.Copyright © 2003, BMJ Publishing Group Ltd. 两类降压药的联合应用 已知某些降压药的联合在某些人群中应用可能 有益,其证据来自: 大型干预试验 以病理生理和血液动力学为基础的研究 JNC-7国外常用降压制剂 ACEI+CCB： 氨氯地平/苯那普利、依那普得/非洛地平 群多普利/缓释维拉帕米 ACEIs+利尿剂： 苯那普利、卡托普利、依那普利、赖诺普利/HCT ARBs+利尿剂： 坎地沙坦、厄贝沙坦、氯沙坦、替米沙坦、缬沙坦/HCT ß-Bs+利尿剂： 氨酰心安、必索洛尔、美多心安/HCT 利尿剂+利尿剂： 复方阿米洛利、安体舒通、氨苯蝶啶/HCT 对于血压高于160/95mmHg的病人, 单一药物治疗通常只能使收缩压下降7-13mmHg, 舒张压下降4-8mmHg 联合应用降压作用相加的药物可使血压降低的幅度大约是单一药物的二倍, 即约降低8-15%, 可使血压为160/95mmHg的患者收缩压下降12-22mmHg, 舒张压下降7-14mmHg 药物合用的机制 ACEI或AIIA+利尿剂：利尿剂激活RAAS，从而使作用于RAAS的ACEI作用更明显。 β-阻滞剂+噻嗪类利尿剂：利尿剂激活肾素，增快心率作用可被β-阻滞剂抵消，而β-阻滞剂缩血管及促肾潴钠作用被噻嗪类利尿剂所抵消； ACEI或AIIA+CCB+利尿剂：阻断RAS后可使三药起协同作用。 可能不适当的药物配伍 β受体阻断剂＋非二氢吡啶类钙拮抗剂 β受体阻断剂＋ACEI或AIIA   血管紧张素 I 血管紧张素 （肝） 血管紧张素 II ARB AT1 受体拮抗剂 Adapted from: de Gasparo et al. Pharmacol Rev. 2000; 52: 415 ACE ARB作用示意图 血管收缩 血管增生 醛固酮分泌 心肌细胞增生 交感张力增加 炎症 氧化应激 血管舒张 抗增殖作用 凋亡 ACEI 不能阻断 Ang I 通过心脏组织中糜酶旁路途径转换为Ang II 。 相反, 缬沙坦选择性地并完全地抑制 Ang II 与 AT1 受体的结合。 肾小管功能和噻嗪类利尿剂作用部位 噻嗪类利尿剂作用于远曲小管近端和袢升支远端，抑制该处Na+重吸收 利尿剂，如氢氯噻嗪与ARB有良好的协同作用： 利尿剂可以减少血浆容量从而降低血压，但是血浆容量降低会激活RAAS系统，由此导致的血管收缩和醛固酮分泌增加会部分抵消利尿剂的降压作用，ARB抑制RAAS系统，从而在降压方面与利尿剂产生协同作用 ARB+利尿剂 ——高血压容量机制与RAS机制的双重阻断 ★ ARB通过改善心输出量，而抵消利尿剂体位性低血压的副作用。 ★ ARB改善肾血流量，而抵消利尿剂因肾小球滤过率 （GFR）下降而引起的副作用，如血尿酸、血钙增加 ★ ARB通过阻断RAS系统，而抵消利尿剂因醛固酮增加引起的副作用，如低血钾等 ARB有效抵消噻嗪类利尿剂的副作用 一种合理的降压配方：ARB+利尿剂，国际循环，2005，4，14 血容量 心输出量 肾血流量 肾素活性 体位性低血压 GFR  肾前性氮质血症 肾小管尿酸和钙的重吸收 醛固酮 低血钾 糖耐量 血尿酸 血钙 利尿剂 ARB LDL-C  固定小剂量复方 血压正常化早 调整降压治疗时波动减小 使病人依从终身治疗的意愿增强 代价降低 固定小剂量复方的优点 总 结 ★多种药物联合治疗是降压治疗中非常有效的手段，尤其对于单药难于控制血压的中重度高血压患者 ★ 降压药物的联合应用既加强了降压作用，又减少了副作用的发生。 ★ 固定小剂量复方制剂减少服药数量，增加患者依从性 谢谢各位专家 首都医科大学宣武医院 华 琦 Methods：56 patients, mean blood pressure 161/98 mm Hg,entered the rotation, of whom 36 received all four monthly cycles of treatment with an angiotensin-converting-enzyme (ACE) inhibitor (A), _-blocker (B), calcium-channel blocker (C), and diuretic (D). Each patient’s best drug was then repeated to assess repeatability. Two measures of individual variability in response were used. First, the value of rotation was measured by the ncreased proportion of patients reaching target blood pressure on their best drug versus their first drug. Second, we assessed whether the responses to each drug were correlated with each other. Findings： Significant variability in response was found. 20 of the 41 patients reaching target blood pressure (_140/90mm Hg) failed to achieve this target on their first drug. Rotation increased from 22/56 (39%) to 41/56 (73%) the success of monotherapy (p=0·0001); in half the patients, blood-pressure on the best treatment was 135/85 mm Hg or less. There were significant correlations between the blood pressure responses to A and B (r=0·5, p<0·01), and C and D (r=0·6, p<0·001), but not between the other four pairings of treatments. The responses to the AB pair were, on average, at least 50% higher than those to the CD pair;this difference was highly significant by multivariate in individual responses to the different agents. A few investigators have observed such variability during crossover studies,2–7 and systematic rotation through each class has been suggested as the most logical, if laborious, approach to treatment.8,9 However, to our knowledge no prospective rotation study of the four main classes of antihypertensive drugs has previously been done. BMJ  2003;326:1427 (28 June), doi:10.1136/bmj.326.7404.1427 Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials M R Law, professor1, N J Wald, professor1, J K Morris, senior lecturer1, R E Jordan, research assistant1 Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. Subjects 40 000 treated patients and 16 000 patients given placebo. Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69. 前面谈到抗高血压药物联合治疗是必不可少的治疗选择,下面我们将探讨处方临时联合与固定剂量联合哪一种方法更具优越性? (读片)—再次强调收缩压控制的重要性 A basic principle of pharmacology is that drugs are following the log-linear dose-dependent curve. That means that, the higher the dose of a drug, the greater its therapeutic action and toxicity. At low doses the therapeutic effect is much higher than the toxic effect. So, application of this pharmacological principle suggests that an equally rational approach in therapy is to use a combination of low doses of two drugs with complementary mechanisms of action. Monotherapy relies on increasing the dose when the patient does not respond, thereby increasing side effects. A low-dose combination relies on combining drugs with complementary modes of action to obtain a higher responder rate and a lower rate of side effects. Because many, and probably most, side effects are dose-related, and because side effects differ between classes of antihypertensives, it follows that when an equal antihypertensive effect is obtained by the fixed low-dose combination of two drugs from two different classes, the side-effect profile is lower. And it is particularly attractive with a combination of drug classes that in themselves have an excellent tolerability profile (such as the ACE inhibitor perindopril and a diuretic without metabolic side effects such as indapamide). Calculated as difference between treated and placebo groups in proportion of participants who developed one or more symptoms, excluding headaches, which were significantly less common in people receiving treatment.Commonest symptoms: thiazides—dizziness, impotence, nausea, muscle cramp; β blockers—cold extremities, fatigue, nausea; ACE inhibitors—cough; calcium channel blockers—flushing, ankle oedema, dizziness.7BMJ. 2003 June 28; 326(7404): 1427.Copyright © 2003, BMJ Publishing Group Ltd. ACEI 不能阻断 Ang I 通过心脏组织中糜酶旁路途径转换为Ang II 。 相反, 缬沙坦选择性地并完全地抑制 Ang II 与 AT1 受体的结合。