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ACC/AHA　成人慢性心力衰竭的诊断和治疗指南

发布于:2007-12-12 09:55

（2005年8月） ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult（2005） Sharon Ann Hunt, MD, FACC, FAHA, Chair 北京安贞医院：韩智红　姚海木　张晓霞　吕强　译北京安贞医院：吴学思　审校 1目录序言　1. 前言　　　2. 心力衰竭作为临床综合征的特点　　　　　2.1. 心力衰竭的定义　　　　　2.2. 心力衰竭是一种症状性疾病　　　　　2.3. 心力衰竭是一种不断发展的疾病　　　3. 有心力衰竭表现患者的临床评价　　　　　3.1. 患者的最初评价　　　　　3.1.1. 识别心力衰竭患者　　　　　3.1.2. 识别患者结构与功能的异常　　　　　3.1.3. 引起心力衰竭的原因评价　　　　　3.1.3.1. 病史与体格检查　　　　　3.1.3.2. 实验室检查　　　　　3.1.3.3. 冠心病可能性的评价　　　　　3.1.3.4. 心肌病可能性的评价　　　　　3.2. 患者的进一步评价　　　　　3.2.1. 功能评价　　　　　3.2.2. 容量状态评价　　　　　3.2.3. 实验室评价　　　　　3.2.4. 预后评估　　　4. 治疗　　　　　4.1. 有发展为心力衰竭高度危险的患者（阶段A）　　　　　4.1.1. 控制危险因素　　　　　4.1.1.1. 治疗高血压　　　　　4.1.1.2. 治疗糖尿病　　　　　4.1.1.3. 治疗代谢综合征　　　　　4.1.1.4. 治疗粥样硬化性疾病　　　　　4.1.1.5. 控制可能引起心肌损伤的情况　　　　　4.1.1.6. 其他措施　　　　　4.1.2. 结构异常的早期识别　　　　　4.2. 有心脏结构异常或重塑但尚无心力衰竭症状的患者（阶段B）　　　　　4.2.1. 心血管事件的预防　　　　　4.2.1.1. 急性心肌梗死的患者　　　　　4.2.1.2. 有心肌梗死病史但LVEF正常的患者　　　　　4.2.1.3. 高血压与左室肥厚的患者　　　　　4.2.1.4. 没有症状的慢性左室收缩功能不良患者　　　　　4.2.1.5. 无症状的严重瓣膜病患者　　　　　4.2.2. 心力衰竭的早期识别　　　　　4.3. 目前或曾经有心力衰竭症状的患者（阶段C）　　　　　4.3.1. LVEF减低的患者　　　　　4.3.1.1. 一般措施　　　　　4.3.1.2. 常规药物　　　　　4.3.1.2.1. 利尿剂 2 　　　　　4.3.1.2.2. 肾素-血管紧张素-醛固酮系统抑制剂　　　　　4.3.1.2.2.1. 血管紧张素转化酶抑制剂　　　　　4.3.1.2.2.2. 血管紧张素受体阻滞剂　　　　　4.3.1.2.2.3. 醛固酮受体拮抗剂　　　　　4.3.1.2.3. β-肾上腺素能受体阻滞剂　　　　　4.3.1.2.4. 洋地黄　　　　　4.3.1.2.5. 抗室性心律失常药物与猝死的预防　　　　　4.3.1.3. 特定的患者可考虑应用的方法　　　　　4.3.1.3.1. 硝酸异山梨酯　　　　　4.3.1.3.2. 肼苯哒嗪　　　　　4.3.1.3.3. 肼苯哒嗪与硝酸异山梨酯　　　　　4.3.1.3.4. 心脏再同步化治疗　　　　　4.3.1.3.5. 运动训练　　　　　4.3.1.4. 正在进行研究的药物与治疗　　　　　4.3.1.4.1. 呼吸支持技术　　　　　4.3.1.4.2. 体外反搏　　　　　4.3.1.4.3. 加压素受体拮抗剂　　　　　4.3.1.4.4. 植入式血流动力学监测　　　　　4.3.1.4.5. 心脏支持装置　　　　　4.3.1.4.6. 正在研究的外科方法　　　　　4.3.1.4.7. 奈西立肽　　　　　4.3.1.5. 未证实有效与不支持应用的药物和治疗　　　　　4.3.1.5.1. 营养补充与激素治疗　　　　　4.3.1.5.2. 间断静脉正性肌力药物　　　　　4.3.2. LVEF正常的心力衰竭患者　　　　　4.3.2.1. 患者的识别　　　　　4.3.2.2. 诊断　　　　　4.3.2.3. 治疗原则　　　　　4.4. 终末期顽固性心力衰竭患者（阶段D）　　　　　4.4.1. 体液潴留的治疗　　　　　4.4.2. 神经体液抑制剂的使用　　　　　4.4.3. 静脉血管扩张剂和正性肌力药物　　　　　4.4.4. 机械和外科方法　　　5. 特殊人群的治疗　　　　　5.1. 女性和男性　　　　　5.2. 种族问题　　　　　5.3. 老年患者　　　6. 有伴随疾病的心力衰竭患者　　　　　6.1. 心血管疾病　　　　　6.1.1. 高血压、高脂血症与糖尿病　　　　　6.1.2. 冠状动脉疾病　　　　　6.1.3. 室上性心律失常　　　　　6.1.4. 血栓栓塞事件的预防　　　　　6.2. 非心血管疾病 3 　　　　　6.2.1. 肾功能不全　　　　　6.2.2. 肺部疾病　　　　　6.2.3. 肿瘤　　　　　6.2.4. 甲状腺疾病　　　　　6.2.5. 丙型肝炎与HIV 　　　　　6.2.6. 贫血　　　7. 终末期问题　　　8. 临床指南的实施　　　　　8.1.医疗人员个人的治疗干预　　　　　8.2.疾病治疗系统　　　　　8.3.工作实绩检测　　　　　8.4.全科医生与心脏科医生的作用　　　参考文献－－－－－－－－－－－－－－－－－－－－－－－－－ 序言 　　疾病的诊断、治疗或预防手段应用于临床的过程中，医务人员对这些诊断步骤与治疗的评价起重要的作用。严谨专业地分析正性或负性的相关资料有助于制定指南，从而提高治疗的有效性，改善患者的预后，并通过最有效的治疗而降低医疗费用。　　美国心脏病学会（ACC）和美国心脏学会（AHA）从1980年开始联合制定心血管领域的指南，具体工作由ACC/AHA临床指南专家委员会实施，其作用是建立并修改心血管领域重要的疾病与措施的实施指南。相关专题的专家来自这两个学会，负责综合相关资料并撰写或修改相应的指南。该过程还包括了其他一些医务工作者和相关组织的成员。撰写组重点负责完成正式的文献综述，权衡支持与反对某项治疗或措施的证据和综合已有资料估测预后。患者的特殊情况、伴随疾病和患者对某些观念的喜好可能对检查和治疗的选择、随访的频率及效费比产生影响。如果可能，还应考虑研究中的花费情况，但是，有效性与临床预后是制定指南最首要的依据。ACC/AHA临床指南专家委员会尽量避免偏袒有争议的观点或编写人员的个人观点，特别是要求所有编写人员公开评价不同的观点。这些观点经过高级专家委员会评审，并在每次会议中口头告知所有编写人员，如有变化，编写组会根据情况进行制定。　　临床指南制定的目的是指导帮助临床医生对于特定疾病与临床状态的诊断、治疗或预防。这些指南反映的是专家根据目前有证据的资料达成的一致建议，目的是尽量满足大多数患者在大多数情况下的需要，改善患者的治疗情况及使患者获得最大益处，对于某个特定患者的最终判断应根据患者的具体情况由医生与患者决定。　　这些指南有ACC和AHA管理部门批准发行，并通过美国胸科学会、国际心肺移植学会与心脏节律学会的同意。ACC/AHA指南工作组在指南发行后每年回顾一次，直至重新制定、修改或撤出。本指南的摘要将同时发表在2005年9月20日的美国心脏病学会杂志（JACC）与循环杂志（Circulation）上。其全文公布在ACC（www.acc.org）与AHA（www.my.american-heart.org）网站上，可通过上述两个组织获得全文和摘要。 ACC/AHA临床指南专家委员会主席Elliott M. Antman，MD，FACC，FAHA 1. 前言心力衰竭已成为美国主要的公共卫生问题。美国的心力衰竭患者约有500万，每年新增55万[1]，并可造成每年1200-1500万次临床就诊，总住院天数达650万[2]。1990年至1999年，以心力衰竭作为首要诊断的年住院次数由81万增加到100万，作为首要诊断或次要诊断的由240万增加到360万[3]，2001年，死于心力衰竭的患者约有5.3万。尽管心力衰竭的治疗有很大的进展，但死于心力衰竭的患者数目还在逐步上升，其部分原因是由于急性心肌梗死治疗的进步，存活者增多[1]。　　心衰竭主要是一种老年人疾病[4]，因此人口的老龄化也是心力衰竭发生率增加的原因。年龄超过65岁的老年人中，心力衰竭的发生率约为1%[1]，因心力衰竭住院的患者约80%年龄大于65岁[5]。心力衰竭已成为最常见的医疗卫生诊断相关人群（dignosis-related group），用于心力衰竭诊断与治疗的医疗支出高于其他疾病[6]。2005年其直接与间接花费约为279亿美元[1]，每年应用于心力衰竭药物治疗的花费约为29亿美元[1]。　　ACC与AHA于1995年首次公布了心力衰竭的诊断与治疗指南，并于2001年进行了修订[7]，从那时起，围绕此种常见、花费高、致残并潜在致死的疾病，开展了大量有关药物与非药物治疗的研究，可选择的治疗方法增加，这种增加使得临床决策更难作出，起始治疗的时机、次序，以及各种治疗合用的合理性尚未确定。对于存在LVEF正常的心力衰竭患者这一认识也在不断增加，对于这一部分重要人群的有证据依据的治疗还很少这一事实，也广为重视。由于这些原因，两个组织认为应该重新评价并修订指南，对于心力衰竭治疗最佳选择的认识尚不完善，有待于不断补充与修订。写作组包括15名成员，代表了ACC与AHA，以及美国胸科医师学会、美国心力衰竭学会、国际心肺移植学会、美国家庭医生学会和美国内科医师学会。包括学术与个人实践中的问题。该指南的审阅人包括ACC指定的3名、AHA指定的3名、美国家庭医生学会指定的1名、美国胸科医生学会指定的2名、美国内科医生学会指定的1名、美国心力衰竭学会指定的4名、国际心肺移植学会指定的1名，还有的9名来自ACC/AHA心力衰竭执行委员会、ACC/AHA急性心肌梗死指南制定修改委员会、ACC/AHA/ESC房颤指南制定委员会、ACC/AHA 　　冠脉旁路手术指南委员会、ACC心力衰竭标准委员会、AHA治疗质量与预后研究委员会、AHA心力衰竭与移植委员会。在ACC与AHA的网站上，有2个版本的指南全文，其中1个版本将建议中的变化作为重点，即只将2005年版与2001年版中建议的不同点罗列出来，而省去了那些支持改变的证据与图表。　　在2001年版中，撰写组采用了一种新的心力衰竭的分级方法，该方法同时强调心力衰竭的发生与进展，因此它将心力衰竭分为4个阶段。前2个阶段（阶段A与B）的患者并无心衰，但是医务工作者应该重视的发生心力衰竭的高危人群，阶段A与B最好的定义是具有发生心力衰竭高度危险的患者，例如，冠心病、高血压、糖尿病而未有左室功能受损、心肌肥厚或心腔几何形态变形的患者属于阶段A；而有左室肥厚和/或左室功能受损的无症状患者属于阶段B；阶段C为过去或目前有心力衰竭症状并有心脏结构改变的患者（大多数的心衰患者属于此类）；阶段D为顽固性心力衰竭需要特殊加强的治疗者，如应用机械循环支持、液体移出操作、持续静脉正性肌力药物、心脏移植或新发明的与正在研究的外科方法、临终关怀等。　　该分级方法包括了将会发展为心力衰竭的有危险因素和心脏结构变化的阶段，在左室功能不全或症状出现之前便采取治疗措施可降低心力衰竭的病残率和死亡率。该分级方法是纽约心脏病协会（NYHA）心功能分级方法的补充而不是替代，NYHA分级是对该分级中的阶段C与D的患者症状严重性的分级。多年来已经认识到NYHA分级具有医生的主观判断，而且短时间内可以有很大变化，不同级别的病情治疗差异不大。因此，委员会认为需要一种稳定的阶段分级系统来客观地评价患者饿的病情进展情况，针对不同阶段进行相应的治疗。根据新的分阶段方法，患者的病情可能不进展或只能向更高一级进展，疾病可通过治疗减慢或停止进展，但一般不会发生自发的逆转。例如，一个有临床症状的心力衰竭患者（阶段C）随着治疗或疾病的进展可以有不同的症状分级（NYHA），但他永远也不会回到阶段B（从未发生心力衰竭），阶段C所推荐的治疗他全部适用，尽管他的NYHA分级是Ⅰ级。这种新的分级方案扩展了我们对心力衰竭的思路，与其他一些疾病的分级方法有些类似（例如肿瘤的分级方法）。　　ACC/AHA对于建议分类与证据等级的描述如下。　　建议分类： Ⅰ类：有证据和／或共识证实采取的诊断措施／治疗实用并有效。 Ⅱ类：采取的措施／治疗的实用性和有效性的证据有矛盾和／或观点有分歧。 Ⅱa类：证据／观点倾向于实用／有效。 Ⅱb类：证据／观点不倾向于实用／有效。 Ⅲ类：有证据和／或共识证实采取的措施／治疗无实用性／无效并且在某些病例可能有害。　　证据等级： A级：资料来自多项随机临床试验或荟萃分析； B级：资料来自单个随机临床试验或大的非随机研究； C级：专家共识的意见和／或小规模的研究。　　本指南的建议尽可能采用循证医学作为证据，相关的医学术语应用英语的表达方式经过一系列计算机检索（包括Medline和EMBASE）并人工检索了一部分文章，所列出的参考文献具有代表性但并非全部。对于某类药物的建议也是指具体有循证医学证据证实有效的药物，除非公认这类药物有广泛的类效应。　　委员会把本指南的重点锁定为心力衰竭的预防及成人LVEF正常或减低的慢性心力衰竭患者的诊断与治疗。本指南没有涉及急性心力衰竭，后者需要制定专门的指南，并且在ACC/AHA急性ST段抬高心肌梗死指南[8]及ACC/AHA不稳定心绞痛和非ST段抬高心肌梗死指南2003[9]中有部分论述。本指南还排除了儿童的心力衰竭，因为儿童心力衰竭的基础疾病与成人不同，并且尚没有包括儿童的治疗心力衰竭的对照研究。本指南也不包括主要由瓣膜病（见ACC/AHA心脏瓣膜病治疗指南[7]）或先天性心脏病引起的心力衰竭，不包括对心脏特异性疾病（例如血色素沉着症、结节病或淀粉样变性）的治疗建议。　　本指南的目的是帮助医务工作者在心力衰竭的预防、诊断和治疗方面提供可选用的方法，为的是在多数情况下满足多数患者的需求，但对于特定患者的最终决定还需医务人员根据情况加以确定。本指南并未从社会学观点上分析费效学，也不能帮助建立合理利用医疗资源的政策，事实上本指南并未考虑资源不足的问题，没有给政策制定者提供资源分配的信息。本指南描述的治疗策略是对每个患者可采纳的治疗方法的罗列，每个患者都是独特的，不仅是因为其心力衰竭的病因与过程不同，还包括其个人和社会对这种疾病的观念。指南只能罗列出有证据依据的决定或建议，这也是本指南的目的。

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Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure. Am J Med 2000;34:320-4. 279. Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534-41. 280. Waagstein F, Caidahl K, Wallentin I, Bergh CH, Hjalmarson A. Long-term beta- blockade in dilated cardiomyopathy: effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation 1989;80:551-63. 281. Gattis WA, O’Connor CM, Leimberger JD, Felker GM, Adams KF, Gheorghiade M. Clinical outcomes in patients on beta-blocker therapy admitted with worsening chronic heart failure. Am J Cardiol 2003;91:169-74. 282. Effects of metoprolol CR in patients with ischemic and dilated 283. cardiomyopathy : the randomized evaluation of strategies for left ventricular dysfunction pilot study. Circulation 2000;101:378-84. 284. Akera T, Baskin SI, Tobin T, Brody TM. Ouabain: temporal relationship between the inotropic effect and the in vitro binding to, and dissociation from, (Na + + K + )-activated ATPase. Naunyn Schmiedebergs Arch Pharmacol 1973;277:151-62. 285. Thames MD. Acetylstrophanthidin-induced reflex inhibition of canine renal sympathetic nerve activity mediated by cardiac receptors with vagal afferents. Circ Res 1979;44:8-15. 286. Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, Kienzle MG. Sympathoinhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 989;80:65-77. 287. Torretti J, Hendler E, Weinstein E, Longnecker RE, Epstein FH. Functional significance of Na-K-ATPase in the kidney: effects of ouabain inhibition. Am J Physiol 1972;222:1398-405. 288. Covit AB, Schaer GL, Sealey JE, Laragh JH, Cody RJ. Suppression of the renin- angiotensin system by intravenous digoxin in chronic congestive heart failure. Am J Med 1983;75:445-7. Gheorghiade M, Ferguson D. Digoxin: a neurohormonal modulator in heart failure? Circulation 1991;84:2181-6. 289. Dobbs SM, Kenyon WI, Dobbs RJ. Maintenance digoxin after an episode of heart failure: placebo-controlled 110 trial in outpatients. Br Med J 1977;1:749-52. 290. Lee DC, Johnson RA, Bingham JB, et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. N Engl J Med 1982;306:699-705. 291. Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol 1988;61:371-5. 292. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. Acomparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989;320:677-83. 293. Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison MC, Jolly MK, for the PROVED Investigative Group. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol 1993;22:955-62. 294. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors: RADIANCE Study. N Engl J Med 1993;329:1-7. 295. Gheorghiade M, Adams KF Jr, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation 2004;109:2959-64. 296. Rahimtoola SH. Digitalis therapy for patients in clinical heart failure. Circulation 2004;109:2942-6. 297. Matsuda M, Matsuda Y, Yamagishi T, et al. Effects of digoxin, propranolol, and verapamil on exercise in patients with chronic isolated atrial fibrillation. Cardiovasc Res 1991;25:453-7. 298. David D, Segni ED, Klein HO, Kaplinsky E. Inefficacy of digitalis in the control of heart rate in patients with chronic atrial fibrillation: beneficial effect of an added beta adrenergic blocking agent. Am J Cardiol 1979;44:1378-82. 299. Farshi R, Kistner D, Sarma JS, Longmate JA, Singh BN. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of five drug regimens. J Am Coll Cardiol 1999;33:304-10. 300. Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol 2003;42:1944-51. 301. Jelliffe RW, Brooker G. A nomogram for digoxin therapy. Am J Med 1974;57:63-8. 302. Adams KF Jr, Gheorghiade M, Uretsky BF, Patterson JH, Schwartz TA, Young JB. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39:946-53. 303. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871-8. 304. Steiner JF, Robbins LJ, Hammermeister KE, Roth SC, Hammond WS. Incidence of digoxin toxicity in outpatients. West J Med 1994;161:474-8. 305. Arnold SB, Byrd RC, Meister W, et al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980;303:1443-8. 306. Gheorghiade M, Hall VB, Jacobsen G, Alam M, Rosman H, Goldstein S. Effects of increasing maintenance dose of digoxin on left ventricular function and neurohormones in patients with chronic heart failure treated with diuretics and angiotensin-converting enzyme inhibitors. Circulation 1995;92:1801-7. 307. Slatton ML, Irani WN, Hall SA, et al. Does digoxin provide additional hemodynamic and autonomic ben

2007-12-12 11:37:09 by: doctor2

4.3.1.2.2. 肾素-血管紧张素-醛固酮系统抑制剂　　ACEI、ARBs和醛固酮受体拮抗剂可以从多个部位对肾素-血管紧张素-醛固系统（RAAS）进行抑制。ACEI在心衰治疗中的作用得到最为广泛的研究，不仅对心衰治疗有益，而且冠心病和其它动脉粥样硬化性血管疾病以及糖尿病肾病均可从ACEI治疗中获益。在慢性ACEI治疗过程中，可产生逃逸现象，部分是由于从其它途径产生的血管紧张素增加，使血管紧张素恢复到正常水平，这种情况下使用ARBs和醛固酮受体拮抗剂可获得更多益处。　　4.3.1.2.2.1. 血管紧张素转化酶抑制剂　　目前尚不清楚ACEI在心衰治疗中的效果是否是仅仅通过抑制血管紧张素II而产生的，因为除抑制RAS系统外，ACEI还可增强激肽的活性以及激肽介导的前列腺素的生成[176-178]。在心衰实验模型中ACEI抑制心肌重构的作用较ARBs更强[179-182]，而且这种有益作用在同时使用激肽受体阻滞剂时被削弱[179,181]。在30个安慰剂对照的临床研究中超过7000名心力衰竭病人参加了对ACEI在心力衰竭治疗中作用的评价[183]。所有这些研究入选的病人均有收缩功能不全（EF＜0.35-0.40），并已应用利尿剂治疗，用或没用洋地黄。这些研究包括各种病人，如女性和老年人，以及各种原因和程度的左室功能不全病人。然而，收缩功能正常的病人，低血压（收缩压低于90mmHg)或肾功能受损(血清肌酐大于2.5mg/L）的病人没有入选或仅占很小比例。分析结果显示，ACEI可以缓解症状、改善临床状态和病人的一般状况[184-195]。另外，ACEI可以降低死亡危险以及死亡或住院的联合危险[193-195]。有轻度、中度或重度心衰症状的病人，不论有无冠状动脉疾病，均可从ACEI治疗中获益。　　ACEI的临床应用 　　病人的选择所有左室收缩功能障碍所致的心力衰竭病人都需应用ACEI，除非有ACEI的禁忌症或不能耐受治疗。由于ACEI对提高生存率有益，应当尽早开始使用并坚持治疗。通常，ACEI与β-受体阻滞剂合用。当前或近期有体液潴留而没有使用利尿剂的病人不能使用ACEI，因为利尿剂可以维持钠的平衡，预防周围和肺水肿的发生[154]。ACEI的使用优于ARBs或直接血管扩张剂[194,196]。不能使用ACEI的情况包括以往使用ACEI曾发生过威胁生命的不良反应（血管性水肿或无尿肾功能衰竭）及妊娠的病人。如果血压较低（收缩压小于80mmHg)、血清肌酐升高（高于3mg/dl)、双侧肾动脉狭窄或血钾升高（大于5.5mmol/L）时应当谨慎使用ACEI。　　另外，处于休克边缘的病人不能使用ACEI。这种病人应首先纠正心力衰竭，待病情稳定后再重新评价ACEI的使用。　　开始和维持治疗 虽然大多数使用ACEI治疗心力衰竭能改善病人存活率的研究是采用依那普利进行的，但目前料显示各种ACEI在控制症状和提高生存率方面没有差别[183]。尽管在抑制组织血管紧张素转换酶方面各种药物之间存在差异，但在临床心力衰竭治疗方面并未显示抑制组织血管紧张素转换酶有何优势。但是，在选择ACEI时，应当倾向于使用经过临床实验证实可以降低心力衰竭或心肌梗死后病人病残率和死亡率的ACEI（卡托普利、依那普利、赖诺普利、哌道普利、雷米普利和群多普利），因为临床研究已经证实了这些药物可以改变病程的治疗剂量。ACEI应当从小剂量开始，如果可以耐受则逐渐增加剂量。开始治疗1-2周检测肾功能和血钾，以后应定期检测，特别是那些以往有低血压、低钠血症、糖尿病、氮质血症或服用补钾药物的病人。由于体液潴留可以降低治疗效果，而体液不足则可增加ACEI的不良作用[160，163]，因此，在开始治疗前及治疗过程中应调整好利尿剂的剂量，大多数病人可以耐受这些药物治疗[193,195] 。　　心力衰竭病人应当使用多大剂量的ACEI？在针对提高生存率的临床对照研究中，ACEI的剂量不是根据病人对治疗的反应制定的，而是达到靶剂量[193-195]。然而，临床实际使用的剂量常常仅相当于推荐的起始剂量而远小于维持剂量，应该按照哪种方法呢？在ACEI的临床对照研究中，如果不能耐受高剂量，则尝试用小剂量或中等剂量。在使用新型治疗心力衰竭药物的对照研究中，通常使用的是中等剂量的ACEI。大剂量ACEI在减少住院危险方面优于小剂量，但在改善症状和降低死亡率方面二者无差别[197,198]。医生应当根据临床试验结果选择可以降低心血管事件的剂量。如果不能使用或耐受大剂量，应当使用中等剂量治疗，两者疗效只有很小差别。更重要的是，不能因为ACEI没有达到靶剂量而延迟使用β-受体阻滞剂。一旦药物剂量递增到一定程度，通常可以维持ACEI的长期治疗。尽管某些病人在使用ACEI后48小时内症状可以改善，但其临床疗效的发挥通常需要数周、数月或更长时间[155,184]。即使症状没有改善，长期使用ACEI也可以降低死亡和住院的危险。突然撤除ACEI治疗可导致临床状况恶化，因此应当避免[199]，除非有威胁生命的并发症（如血管性水肿）。　　在长期使用ACEI治疗的过程中，应尽量避免钠潴留或不足，因为水盐平衡的变化可以增加或降低心血管和肾脏对治疗的反应[160,163]。体液潴留可以削弱ACEI对症状的缓解，而体液不足则可增加低血压和氮质血症的危险。使用ACEI还可避免长期使用补钾剂。非甾体抗炎药物可降低ACEI对心衰病人的疗效，并增加副作用，应避免使用[135,137]。　　临床经验表明，血液动力学或临床状态不稳定的病人使用ACEI引起的低血压，可以削弱病人对利尿剂和静脉血管收缩剂的反应[200,201]。因此，对这些病人（特别是对利尿剂反应差的病人），谨慎的做法是暂时停止ACEI治疗，直到病人临床状态稳定。　　对大规模临床试验的回顾分析显示，阿司匹林可以抑制激肽介导的前列腺素合成，影响ACEI对心力衰竭病人的疗效。在短期的血流动力学和最大运动耐量研究中，阿司匹林可以降低ACEI对心力衰竭病人血流动力学的作用[202,203]，而非阿司匹林抗血小板药物则没有影响[204]。　　在几项多中心研究中，同时使用阿司匹林可减低ACEI对生存率和心血管病残率的益处[205,206]。最近对6个包括22060病人的ACEI随机研究的资料分析重新评价了与阿司匹林合用的潜在有害作用。对这些资料的整体分析发现，无论合用还是不合用阿司匹林，ACEI均可产生有益效果，使用阿司匹林的病人总体危险降低20%，不使用阿司匹林的病人降低29%，差异未达到统计学意义[207]。接下来的另一个回顾性研究也显示ACEI与阿司匹林合用对长期生存率无影响[208]。因此，许多医生认为，当病人有阿司匹林适应症时可以与ACEI合用。　　然而，对这些研究也有不同的解释。一些医生认为ACEI不能与阿司匹林合用，因为没有证据显示它可以降低心力衰竭病人的缺血事件[209,210]，他们认为应该使用其它不影响ACEI疗效的抗血小板药物（如氯吡格雷），并且可以较好的降低缺血事件[211]。然而，氯吡格雷没有作为缺血事件一级预防的指征。阿司匹林与ACEI可能存在重要的相互作用，这个问题目前仍存在争议，尚需进一步研究。　　治疗的风险 大多数ACEI的不良反应是由于该类药物的两种主要药理学作用所致：对血管紧张素的抑制和对激肽的增强作用。也可能发生其它副作用（如皮疹和味觉障碍）。　　与抑制血管紧张素有关的副作用 　　1．低血压 ACEI治疗心力衰竭最常见的副作用是低血压和头晕。几乎所有使用ACEI治疗的病人都会出现没有症状的血压降低，因此常常是只有出现了立位症状、肾功能恶化、视力模糊或晕厥时才引起重视。低血压常常出现于开始治疗的前几天，特别是在低血容量病人、近期大量利尿和低钠血症病人（血钠浓度低于130mmol/L)[212]。　　如果症状性低血压发生于开始剂量，再次使用同样剂量该药物可能并不复发。然而，最好的做法是只要没有明显的体液潴留，可以减少利尿剂的剂量、减少对盐摄入的限制而降低对肾素-血管紧张素系统的依赖。可以减小其它降压药物的剂量（尤其是血管扩张剂），或与ACEI交叉使用，使二者的峰效应错开。大多数早期使用ACEI出现低血压的病人，只要采取适当的措施减少低血压的复发，都适合该类药物的长期治疗。　　2．肾功能恶化 在肾灌注低下的情况下（如心力衰竭），肾小球滤过率主要依赖于血管紧张素介导的出球小动脉的收缩[213]，抑制血管紧张素转换酶可导致肾功能不全[160]。因为失去血管紧张素II的支持后，肾小球滤过率将降低，那些需要肾素-血管紧张素系统的支持而维持肾稳态的病人更易发生氮质血症（如心功能Ⅳ级或低钠血症的病人）[214]。严重心力衰竭的病人使用ACEI治疗有15%-30%的病人血肌酐明显升高（如升高大于0.3mg/dl)[215]，但仅5%-15%的病人出现轻到中度症状[216]。如果病人有双侧肾动脉狭窄或正在服用非甾体类抗炎药物，则危险性明显增加[134,137,217]。此时减少利尿剂的使用量常常可以改善肾功能，而不需要停止ACEI的治疗[160]。然而，如果病人有体液潴留则利尿剂不能减量，在轻度或中度氮质血症时可以不处理，继续ACEI治疗，密切观察病情变化。　　3．钾潴留 心力衰竭病人使用ACEI可能出现严重的高钾血症，严重时可引起心脏传导障碍。一般情况下，高钾血症出现于肾功能恶化、口服补钾制剂或保钾利尿剂或醛固酮受体拮抗剂的病人，特别是糖尿病病人[218]。　　与激肽激活有关的副作用 　　1．咳嗽 使用ACEI所致的咳嗽是其不能长期应用的主要原因[219]；咳嗽的发生率在欧洲白人约5%-10%，而在中国人高达50%[220]。其特点是无痰，常有喉部发痒的感觉，常出现于治疗的第一个月内，停药后1-2周消失，再次服药后数天又出现。只有在排除其它原因的咳嗽，例如肺淤血后才考虑为ACEI所致。停药后咳嗽消失，再次使用其它ACEI制剂时又出现咳嗽的现象，强烈提示咳嗽由ACEI所致。有几项研究发现，再次服药时并不发生咳嗽，可能是巧合，由于该类药物长期使用很有益处，只要咳嗽不是很重，应鼓励病人坚持治疗。只有咳嗽持续发生且不能耐受时才考虑停用ACEI，换用其它药物（如ARB）。　　2．血管性水肿 血管性水肿在服用ACEI的病人中发生率不到1%，但黑人发生率较高。由于其发生可能威胁生命，所有怀疑出现该反应的病人应终生避免使用ACEI[210]。有血管性水肿史的病人不应尝试使用ACEI。虽然对于使用ACEI发生血管性水肿的病人可以考虑使用ARBs替换，但也有病人使用ARBs时也发生血管性水肿，因此，对于使用ACEI发生血管性水肿的病人换用ARBs时应极度谨慎[211-213，223a]。　　4.3.1.2.2.2. 血管紧张素受体阻断剂　　ARBs的发展基于以下原因：1）在ACE被抑制时，通过替代途径，血管紧张素II（AngⅡ）仍持续产生；2）抑制RAS而不抑制激肽酶，可以产生与ACEI同样的益处，而且可减少发生不良反应的危险[224]。由于在心力衰竭治疗中，ACEI的激肽积聚效应产生的有益作用较抑制AngⅡ形成的作用更大[225]，而一些副作用则与抑制AngⅡ形成有关[179,181]。表6列举了心力衰竭治疗中常用的RAAS抑制剂和β-受体阻滞剂。

2007-12-12 12:11:17 by: doctor2

－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－ 药物　　　　　　　　　　　　起始剂量（日）　　　　　　　　最大剂量（日） ACEI 　卡托普利　　　　　　　　　　6.25mg,　3次　　　　　　　　　　50mg,　3次　依那普利　　　　　　　　　　2.5mg,　2次　　　　　　　　　　10-20 mg,　2次　福辛普利　　　　　　　　　　5-10mg,　1次　　　　　　　　　　40mg,　1次　赖诺普利　　　　　　　　　　2.5-5mg,　1次　　　　　　　　　20-40mg,　1次　哌道普利　　　　　　　　　　2mg,　1次　　　　　　　　　　　8-16mg　1次　喹那普利　　　　　　　　　　5mg,　2次　　　　　　　　　　　20mg　2次　雷米普利　　　　　　　　　1.25-2.5mg,　1次　　　　　　　　　10mg　1次　群多普利　　　　　　　　　　1mg,　1次　　　　　　　　　　　4mg,　1次 ARBs 　坎地沙坦　　　　　　　　　　4-8mg,　1次　　　　　　　　　　32mg,　1次　氯沙坦　　　　　　　　　　　25-50mg,　1次　　　　　　　　　50-100mg,　1次　缬沙坦　　　　　　　　　　　20-40mg,　2次　　　　　　　　　160mg,　2次 醛固酮拮抗剂 　螺内酯　　　　　　　　　　　12.5-25mg,　1次　　　　　　　　25mg,　1-2次　依普利酮　　　　　　　　　　25mg,　1次　　　　　　　　　　50mg,　1次 β受体阻滞剂 　比索洛尔　　　　　　　　　　1.25mg,　1次　　　　　　　　　10mg,　1次　卡维地洛　　　　　　　　　　3.125mg,　2次　　　　　　　　25mg,　2次　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　50mg, (体重超过85公斤)　2次　缓释琥珀酸美托洛尔　　　　　12.5-25mg,　1次　　　　　　　200mg,　1次－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－

2007-12-12 12:53:30 by: doctor2

目前临床已经使用数种ARBs（如坎地沙坦、依普沙坦、依贝沙坦、氯沙坦、替米沙坦、奥美沙坦和缬沙坦）。但这些药物在临床对照研究中治疗心力衰竭病人的经验不及ACEI。然而，在几个安慰剂对照研究中，长期使用ARBs治疗所产生的血液动力学、神经体液和临床疗效与抑制RAS的疗效相似[226-231]。最近的一个试验显示，心肌梗死后早期合并左室功能异常的病人使用ARBs具有与ACEI同样的益处，但两者的耐受性没有差别[110]。然而，ARBs与ACEI合用对结果没有改善，还增加副作用。　　对因咳嗽或血管性水肿而不能耐受ACEI的病人，已经证明ARBs类缬沙坦和坎地沙坦可降低住院率和死亡率[223,232]。联合使用ARBs和ACEI可进一步减小左室容积[233]。　　在另外两个研究中，在慢性ACEI治疗基础上加用ARBs可轻度降低住院率，其中一个研究有降低死亡率的趋势，而在另一个研究中对死亡率无影响[232-234]。　　血管紧张素受体阻断剂的使用建议 　　在慢性心力衰竭治疗中，ACEI仍然是抑制肾素-血管紧张素系统的第一选择，但ARBs可作为替代药物使用。在CHARM Preserved 研究中，坎地沙坦可以改善不能耐受ACEI且左室收缩功能正常病人的预后[235]。与ACEI一样，血管紧张素受体阻断剂也可产生低血压、肾功能恶化和高血钾。　　虽然ARBs很少发生血管性水肿，亦有对ACEI和ARBs均发生血管性水肿的病例[223]。虽然ARBs与ACEI和醛固酮拮抗剂联用的资料很少，但联合应用将进一步增加肾功能异常和高钾血症的发生率。目前尚不推荐3种肾素-血管紧张素系统抑制剂常规同时使用。　　ARBs的临床应用 　　起始与维持 血管紧张素受体阻断剂的起始剂量见表6。使用ARB需注意的问题许多与前面介绍的ACEI一样，开始用药后1-2周要复查血压（包括体位性血压变化）、肾功能和血钾，特别是在调整剂量时更应密切观察。收缩压低于80mmHg、低血钠、糖尿病和肾功能受损的病人在使用RAAS受体阻断剂时进行相应检测尤其重要。对于病情稳定的病人，在ACEI或ARBs达到靶剂量前可以加用β-受体阻滞剂。使用ARBs的危险与血管紧张素的抑制有关，当与ACEI或醛固酮受体阻断剂合用时发生低血压、肾功能异常和高血钾的危险明显增加。　　4.3.1.2.2.3. 醛固酮受体拮抗剂　　虽然短期使用ACEI和ARBs均可降低循环醛固酮水平，但在长期治疗中这种抑制并不能持续［236］。实验资料显示，醛固酮对心脏结构和功能的不良影响独立于血管紧张素Ⅱ，因此，长期抑制醛固酮的作用具有重要意义［237-243］。　　螺内酯是最常用的醛固酮受体拮抗剂，在一项大规模的长期临床试验中，NYHA心功能Ⅳ级或心功能Ⅲ级的近期住院患者在使用ACEI的基础上加用小剂量的螺内酯（起始剂量12.5mg），经过2年的治疗，死亡危险从46％降至35％（相对危险下降30％），因心衰住院率下降35％。起始入选病人肌酐低于2.0mg/dL,而整个实验中多数病人低于2.5mg/dL，入选后停止补钾制剂，密切观察血钾和肾功能的变化。　　最近的一个试验研究了新的醛固酮受体拮抗剂依普利酮在LVEF≤40％的心衰患者或心肌梗死后14天的糖尿病患者中的疗效。一年死亡率从13.6％降至11.8％，高血钾在依普利酮和安慰剂组的发生率分别为5.5％和3.9％，肌酐清除率小于50ml的发生率分别为10.1％和4.6％［98］。　　使用醛固酮受体拮抗剂的建议有中重度心衰症状以及近期失代偿的病人或心肌梗死早期左室功能异常的病人可以加用小剂量的醛固酮受体拮抗剂。这些建议是基于使用醛固酮受体拮抗剂可以降低死亡和再住院率的2个临床试验结果[98,141]。这两个试验制订的入选标准包括的人群范围较广，而实际入选的病人较为局限，因此，有关的效益-毒性比不一定适用于所有病人。这两个试验都不包括肌酐超过2.5mg/dL的病人，而实际入选的病人中很少超过1.5mg/dL。在有关心肌梗死病人的试验中，依普利酮的益处与血肌酐水平明显相关，入选病人的平均肌酐水平为1.1mg/dL，对超过此水平的病人的生存率无明显益处。　　为了减少心衰病人发生威胁生命的高钾血症的危险，起始治疗时血肌酐浓度应低于2.0-2.5mg/dL，且近期没有恶化；血钾应低于5.0mEq/dL,且没有严重高钾史。鉴于在心肌梗死后早期LVEF较低的病人和近期失代偿且症状较重的病人中使用醛固酮受体拮抗剂的有益证据，具有轻、中度心衰症状的病人在应用袢利尿剂的基础上可以使用醛固酮受体拮抗剂，但写作委员会强烈认为提供这一建议的证据尚不充分，因为尚缺乏在不使用袢利尿剂时应用醛固酮受体拮抗剂的安全性和有效性的证据，目前尚不推荐在不使用其它利尿剂的情况下对慢性心衰患者使用醛固酮受体拮抗剂治疗。虽然在CHARM add 试验中有17%的病人使用螺内酯，但ACEIs、ARBs和醛固酮受体拮抗剂合用的安全性的证据尚不充分，目前不推荐联合应用。　　醛固酮受体拮抗剂的临床应用 　　病人选择　是否使用醛固酮受体拮抗剂要考虑其降低死亡率及因心衰再住院的益处和发生威胁生命的高钾血症的危险。对于那些近期有肾功能不全病史，表现为肌酐升高、尿素氮显著升高或高钾血症，尤其是正在使用胰岛素治疗的糖尿病病人，即使符合推荐标准也不能使用醛固酮受体拮抗剂。血肌酐水平常低估肾功能异常的程度，尤其是老年病人，估计肌酐清除率小于50ml/分钟时应将螺内酯起始剂量调至12.5mg/天或依普利酮25mg/天，当肌酐清除率小于30ml/分钟时应停止使用醛固酮受体拮抗剂（表7）。长期使用大剂量利尿剂而未给补钾制剂的病人要密切观察，因为这些病人可能存在钾代谢异常。　　使用醛固酮受体拮抗剂的危险主要危险是抑制钾的排泄引起的高钾血症。肾功能异常可能恶化，进一步损害钾的排泄。最近一个试验的有益结果导致螺内酯在心衰患者中的使用更加广泛，一项调查报道的继发高钾发生率高达24%[312]，其中一半病人的血钾超过6mEq/L。挪威也有同样的报道[245]。虽然这远高于大型试验中报道的2%的发生率，但与早期报道的13%（25mg）和20%（50mg）的发生率具有可比性。　　对加拿大安大略省因心衰住院后服用ACEI的3万多病人的资料分析显示了其对总体心衰人群的潜在影响。1999年公布这些试验结果后，这一地区螺内酯的处方量上升了三倍多，因高钾血症的住院率从每千人2.4人次增加到11人次，相关死亡率从每千人0.3人次增加到2人次[246]。这些观察结果强烈建议对醛固酮受体拮抗剂的使用须谨慎选择病人，并密切监测。因为进行临床试验的人群是经过严格选择的，当把这些试验结果应用于一般人群时，发生毒性反应的几率显著增加。虽然醛固酮受体拮抗剂的利尿作用较弱，一些病人加用醛固酮受体拮抗剂可显著增强其它利尿剂的作用，导致低血容量，进一步增加肾功能异常和高钾血症的发生率。在慢性稳定治疗阶段，如胃肠炎等引起血容量减少的情况均可引起高钾血症。新型的醛固酮受体拮抗剂依普利酮较少发生男子乳房发育或抗雄性激素效应[98]。　　治疗的开始和监测　螺内酯的起始剂量一般为12.5mg-25mg/日，偶尔可隔日给予。依普利酮在一项心肌梗死后患者的研究中起始剂量为25mg/日，逐渐加量至50mg/日。开始治疗后一般停止使用补钾制剂，劝告患者避免食用高钾食物。然而，先前需要大剂量补钾制剂的患者仍需补钾，特别是曾经发生过低钾性心律失常的患者，但可以减小剂量。另一方面，由于液体潴留而需快速利尿的患者需要补充钾制剂，一旦达到体液平衡就可停止使用。应避免使用非甾体抗炎药物和环氧化酶-2抑制剂，因为可引起肾功能恶化和高钾。开始使用醛固酮受体拮抗剂治疗后3天和1周需测定血钾和肾功能，之后可根据肾功能和体液平衡情况定期检测，但前3个月至少每月一次，之后每3个月一次。当ACEI或ARBs加量时，应重新按上述方法开始检测。考虑到发生高钾的危险，写作委员会建议避免ACEs、ARBs和醛固酮受体拮抗剂联合使用。若血钾超过5.5mEq/L应停止加量或减小醛固酮受体拮抗剂剂量，如果病人服用补钾制剂，应首先停止补钾制剂，然后根据情况调整醛固酮受体拮抗剂剂量。若发生肾功能恶化，应重新评价治疗方案并考虑停止使用醛固酮受体拮抗剂。应告诉病人在发生腹泻或停用袢利尿剂时停止使用醛固酮受体拮抗剂。

2007-12-12 12:59:44 by: doctor2

－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－ 1.肾功能损害是醛固酮受体拮抗剂治疗过程中发生高钾血症的一个危险因素，肌酐超过1.6mg/dL时危险性显著增加。在老年或肌肉量较少的病人，血肌酐水平并不能准确反映肾小球滤过率，肾小球滤过率或肌酐清除率应大于30ml/分。 2.基础血钾水平超过5.0mEq/L的病人不能使用醛固酮受体拮抗剂。 3.起始推荐剂量螺内酯12.5mg或依普利酮25mg，如果合适可增加剂量至螺内酯25mg或依普利酮50mg。 4.同时使用大剂量的ACEI（卡托普利大于75mg/天，依那普利或赖诺普利大于10mg/天）可增加高钾血症的危险。 5.应避免使用非甾体抗炎药物和环氧化酶-2抑制剂（COX-2抑制剂）。 6.应停止使用补钾制剂或减量。 7.应密切检测血钾，开始治疗后3天和1周需测定血钾和肾功能，之后的前3个月至少每月检测一次。 8.及时处理腹泻及其它可引起脱水的原因。＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝

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