心衰指导

心力衰竭治疗近况,上海长征医院心内科 廖德宁,国人不同性别、年龄组成人的心衰患病率(%),国人心衰病因,高血压缺血性心脏病心肌病糖尿病先心,风湿性心脏病高血压心肌病先心营养性心肌病肺心病缺血性心脏病,缺血性心脏病心肌病糖尿病高血压风湿性心脏病先心肺心病,心衰,外在机制：机械、负荷、代谢、营养,Why?,内在机制：细胞、分子、基因,Why?-心衰新概念,心室重塑：一系列复杂的分子和细胞机制导致心肌结构、功能和表型的变化。,胚胎基因和蛋白质再表达,心肌细胞肥大、凋亡，心肌细胞外基质量和组成变化,心肌质量、心室容积和形状改变,神经内分泌和细胞因子,心衰新概念,心衰：血流动力学障碍神经内分泌失调。治疗关键：调控神经内分泌。如果一种药物能够改善疾病进程，不管这种药物是否能够缓解症状，都应尽早使用。如果一种药物仅对于缓解症状有效而不能改善疾病进程，那么最好将这种药物保留到出现症状时再用，而非早期使用。,心力衰竭药物治疗历史,洋地黄和利尿剂时代血管扩张剂时代 -受体阻滞剂、硝酸酯类、小动脉扩张剂及钙通道阻滞剂等非洋地黄类正性肌力药时代 -受体激动剂（多巴酚丁胺等）；磷酸二酯酶抑制剂抗神经内分泌激活时代 ACEI；-受体阻滞剂；醛固酮拮抗剂。,心力衰竭的现代药物治疗,I级： ACEIII级：ACEI利尿剂受体阻滞剂地高辛（？）III级：ACEI利尿剂受体阻滞剂地高辛IV级：ACEI利尿剂受体阻滞剂(慎用)地高辛安体舒通,ACE抑制剂,心衰药物治疗的基石,SOLVD（Studies Of Left Ventricular Dysfunction）结果,ACE抑制剂,迄今为止，已有39个（8308例）ACEI治疗心衰的临床研究，结果都能改善症状、延缓重塑、降低死亡危险性。这些研究奠定了ACEI作为心衰治疗的基石和首选药物地位。,为什么医生不按实证医学使用ACEI？,没有认识到心衰是一种值得治疗的公众健康难题 没有充分体会到ACEI 在心衰治疗中的好处和重要性 没有理解应用AECI所带来的临床益处是超值的 对ACEI 副作用的考量超过对其临床益处的估计认为临床试验中观察到的益处并不能转化到临床实践中没有认识到ACEI能够延缓和改善心衰进程,J. McMurray: Eur Heart J 1998; 19(suppl. L):L15-L21,Failure to Practice Evidence-Based Medicine: Why Do Physicians Not Treat Patients with Heart Failure with ACE Inhibitors?,ACEI使用要点,除非有禁忌或不能耐受均应用（包括I级）必须告知病人疗效数周或数月才出现，即使症状未改善，仍可延缓疾病进展副作用可能早期出现，但不妨碍长期应用从小剂量开始，最好用至最大耐受量需无限期、终生服用长期治疗出现“醛固酮逃逸”,ACEI使用要点,血Cr4mg/dl而未透析者不宜对血Cr1.5mg/dl者，虽然肾小球内压降低可使GFR在短期内下降，但有利于长期更好地维持GFR血Cr升高0.51mg：不必停药；常在12周左右趋于稳定或下降血Cr升高1mg：应减少ACEI及利尿剂剂量容易引起血Cr升高的情况：大剂量利尿、重度心衰、肾动脉狭窄、低血压,常用ACEI的参考目标剂量,药物 起始剂量 目标剂量卡托普利 6.25mg、tid 2550mg、tid依那普利 2.5mg、qd 10mg、bid培哚普利 2mg、qd 4mg、qd苯那普利 2.5mg、qd 510mg、bid福辛普利 10mg、qd 2040mg、qd西拉普利 0.5mg、qd 2.5mg、qd,ARB与ACEI比较的优点,作用具特异性，副反应较小仍保持循环反射，体位性低血压少不论形成AII酶的途径如何,均可阻滞AII作用能完全、直接阻断循环、局部组织AII作用使AII增加，升高的AII加强对AT2的作用不影响缓激肽，无咳嗽副作用但缓激肽亦有益处：增加扩血管的前列腺素、抗增生（ACEI合用ASA减低效果）,ARB的临床应用建议,未用过ACEI和能耐受ACEI者，仍以ACEI为首选用于ACEI不耐受者（少有咳嗽、血管性水肿，其余不良反应同ACEI）对受体阻滞剂有禁忌时，ACEI联用代文,利尿剂,利尿剂的应用要点（1）,控制心衰体液潴留唯一可靠方法 应用于所有伴有体液潴留的、症状性心力衰竭治疗中若出现低血压或氮质血症，应减量或暂停确定剂量和疗效的最好方法: 小剂量开始逐渐加量，使体重每日减轻0.51kg双克100mg/d无意义; 速尿量效呈线性关系病情稳定（浊音、水肿消失，体重稳定）后以小剂量长期维持,利尿剂的应用要点（2）,影响几乎所有抗心衰药物的疗效和毒性剂量不足导致液体潴留减弱ACEI疗效增加阻滞剂的危险 剂量过大导致血容量不足增加ACEI与硝酸盐等低血压的危险增加ACEI与ARB治疗中肾功能不全的危险,利尿剂的应用要点（3）,利尿剂抵抗（伴心衰加重）的对策静脉给药（速尿可持续滴注）改袢利尿剂联合用药短期应用增加肾脏血流量的药物（小剂量多巴胺、多巴酚丁胺）停用非甾体类抗炎药,受体阻滞剂,卡维地洛对重度慢性心衰存活率的影响Effect of Carvedilol on Survival in Severe Chronic Heart Failure,Carvedilol Prospective Randomized Cumulative Survival Study GroupN Engl J Med 2001；344：1651,存活率 KaplanMeier Analysis of Time to Death in the Placebo Group and the Carvedilol Group. The 35% lower risk in the carvedilol group was significant: P=0.00013 (unadjusted) and P=0.0014 (adjusted).,总死亡和首次住院率KaplanMeier Analysis of Time to Death or First Hospitalization for Any Reason in the Placebo Group and the Carvedilol Group. The 24% lower risk in the carvedilol group was significant (P0.001).,撤药率KaplanMeier Analysis of the Time to Permanent Withdrawal of the Study Medication because of Adverse Reactions or for Reasons Other Than Death in the Placebo Group and the Carvedilol Group.,结论,倍他受体阻滞剂不但能够降低轻到中度心衰病人的病残率和死亡率，对重度心衰病人也同样有效。,-受体阻滞剂的使用要点,适应证所有慢性收缩性心衰、心功能II、III级、病情稳定禁忌证支气管痉挛心动过缓，II、III度AVB急性心衰、难治性心衰需向患者交代症状改善需23月即使症状未改善，亦可延缓疾病进展早期可出现不良反应，不影响治疗,-受体阻滞剂的使用要点,“干体重”: 充分利尿，处于利尿剂维持阶段起始剂量：美托洛尔6.25mg、bid；比索洛尔1.25mg、qd；卡维地洛3.125mg、bid、每24周酌情增加剂量宜个体化, 不按治疗反应来定。达到最大耐受量或目标剂量后长期维持。参考目标剂量：美托洛尔75100mg、bid;比索洛尔10mg、qd；卡维地洛25mg、bid,-受体阻滞剂治疗时应监测,液体潴留（体重增加）和心衰恶化：加大利尿心动过缓和房室阻滞：55次/分减量或停药低血压：ACEI或扩血管药减量，不减利尿剂,地高辛,唯一不增加死亡率的正性肌力药物,The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure,The Digitalis Investigation Group,Background The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial. Methods In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-convertingenzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo. Results In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial.,Digoxin 和 Placebo 组总死亡率：地高辛不降低总死亡率,心衰恶化死亡率 Mortality Due to Worsening Heart Failure in the Digoxin and Placebo Groups.,因心衰恶化而死亡或住院：地高辛降低因心衰恶化住院率 Incidence of Death or Hospitalization Due to Worsening Heart Failure in the Digoxin and Placebo Groups.,地高辛的长期作用,减少住院次数生存率与安慰剂量相仿增加严重心律失常增加心肌梗死,地高辛应用要点,推荐用于改善收缩性心衰的临床症状应与其它三种标准药物联用用于伴快心室率房颤者（控制运动时心室率阻滞剂效果更好）根据血浓度决定用药量依据不足小剂量亦有效多数心衰患者能耐受,醛固酮受体阻断剂：Spironolactone,The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure,The Randomized Aldactone Evaluation Study Investigators N Engl J Med 1999:341:709-17,Background and Methods Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-convertingenzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.,存活率：Spironolactone group vs placebo group: The risk of death was 30% lower (P0.001).,Relative Risks of Death from All Causes and According to Demographic and Clinical Characteristics.The horizontal lines indicate 95 percent confidence intervals.,结论,在标准治疗基础上，加用醛固酮受体阻断剂（螺内酯，spironolactone），可有效降低重度心衰发病率和死亡率。,螺内酯应用要点,用量：12.525mg、qd目前仅用于IV级心功能的治疗螺内酯为非特异性盐皮质激素受体阻断剂，还阻断孕激素和雄激素，副作用大,机制,抑制促进纤维化的机制：PAI1表达，导致血管纤溶的改变；刺激TGFa1、刺激氧自由基,非洋地黄强心剂,维司力农治疗重度心衰：死亡率呈剂量依赖性增加A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure,The Vesnarinone（维司力农）Trial Investigators,维司力农治疗重度心衰：死亡率呈剂量依赖性增加,Background Vesnarinone（维司力农）, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. Methods We enrolled 3833 patients who had symptoms of NYHA class III or IV HF and a left ventricular EF of 30% or less despite optimal treatment. The mean follow-up was 286 days. Results There were significantly fewer deaths in the placebo group (242 deaths, or 18.9%) than in the 60-mg vesnarinone group (292 deaths, or 22.9%) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those