慢性心力衰竭诊断和治疗

• 尽管通过旁路途径血管紧张素I转换为血管紧张素II产生了长期有效的ACE抑制，仍然会出现血管紧张素II逃逸 现象。这些机制包括了人体心脏中的糜蛋白酶、通过糜蛋白酶抑制素敏感性血管紧张素II介导产生的酶和组织 蛋白酶G。非ACE依赖性血管紧张素II合成机制不受ACEI的影响。其它的非肾素途径也可能生成血管紧张素II 。因此有必要测定血管紧张素受体阻断剂的效应，因为血管紧张素受体阻断剂可以通过阻断血管紧张素II与其 受体结合来完全抑制肾素-血管紧张素系统。 • 血管紧张素转换酶不仅可以把血管紧张素I转变成血管紧张素II，也可以把缓激肽降解成无活性片断。应用 ACEI治疗的过程中会出现缓激肽的蓄积，这可能是ACEI副作用产生的原因，如咳嗽、肾功能不全和血管性水 肿。然而，缓激肽也存在有益影响，如NO-介导的血管扩张、通过扩张冠脉和动脉有可能对心衰产生有益影响 、改善左室舒张功能。血管紧张素II受体拮抗剂不能抑制缓激肽的降解，因此不会引起咳嗽、肾功能不全和血 管性水肿。另一方面，它缺乏ACEI类药物由于缓激肽蓄积而产生的有益影响。 • 研究一致显示，长期应用 ACEI类药物可以改善慢性心力衰竭(CHF)患者的血流动力学、症状、体征和运动能 力。两个研究比较了ACEI和安慰剂对CHF患者死亡率的影响。 • 第一个研究名为Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)，这个研究证实了阻断肾 素－血管紧张素系统可以改善预后。这个多中心、随机、双盲、安慰剂对照研究包括253名患者，他们患有严 重的心力衰竭(NYHA class IV) ，而且接受洋地黄和利尿剂的最佳治疗。患者分成依那普利组 (up to 40 mg/day) 和安慰剂组 因为ACEI对早期存活率产生了明显的有益影响 所以研究不得不提前终止 依那普利使6个月内和安慰剂组。因为ACEI对早期存活率产生了明显的有益影响，所以研究不得不提前终止。依那普利使6个月内 的死亡率下降了 40% (p=0.002)，1年的死亡率下降了31% (p=0.001)，通过改善心衰使死亡率下降了50% (p=0.001)。 • 左室功能不全研究 (SOLVD) 治疗试验研究了ACEI类药物依那普利对总体死亡率、CHF住院率和左室射血分数 <35%的患者特殊原因死亡率的影响。试验包括2569名心衰分级为 NYHA class II-III的患者，服用依那普利 5 － 20 mg/天或服用安慰剂。平均随访大约 3.5 年后，依那普利降低了16%的死亡率， (安慰剂为40%－35%, p=0.0036)。另外，依那普利使恶化的CHF患者联合终点事件－死亡或住院的发生率下降了26% (p<0.0001) ，使 心血管事件的住院率下降了10% 。 CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. • ACEI的有利影响也见于左室功能不全或心梗后出现心衰症状的患者。3个大型试验 (SAVE, AIRE, 和 TRACE)随机选取了将 近 6000 名左室功能不全或心衰的患者，他们在急性心梗的3－16天内开始服用ACEI或安慰剂。ACEI治疗将死亡率平均降 低了大约25%。 • 存活率和心室扩大 (SAVE) 试验随机选取了2231名患者，心梗后3－16天内射血分数 <40% ，但不存在心衰的证据或症状。 这些患者服用卡托普利150 mg/天或者安慰剂。平均随访 3.5 年后，ACEI降低了19%所有原因引起的死亡率 (p=0.019)。卡托 普利也使心血管死亡率降低了21% (p=0.014)，使发展到明显CHF的几率降低了37% (p=0.032)，再梗的危险率降低了25% (p )， (p )， (p=0.015)。 • 急性心梗雷米普利有效性 (AlRE) 试验随机选取2006 名急性心梗患者，现出暂时的床旁体征或进行性心衰，如肺充血、 肺水肿或持续性心动过速伴第三心音。心梗后的3-10天内开始服用雷米普利5－10 mg/天或者安慰剂。平均随访15个月后， 雷米普利组降低了27%的所有原因引起的死亡率(p<0.002) 。雷米普利也使主要心血管事件如死亡、严重的或具有耐药性的 心衰、再梗或中风的发生率降低了19% (p=0.008)。 • 群多普利心脏病评估 (TRACE) 试验研究了心梗后3-7天内超声心动图显示左室收缩功能不全的患者。共1749名患者随机分 成群多普利1-4 mg/天组或安慰剂组，随访至少24个月。群多普利组总死亡率降低了24% (p=0.001)。 Pf ff MA B ld E M LA l d h SAVE I i Eff f il li d bidi i i i hPfeffer MA, Braunwald E, Moye LA, et al., and the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669-677. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828. Kober L,Torp-Pedersen C, Carisen JE, et al., and the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670-1676. •尽管 ACEIs 可以有效治疗高血压、延缓CHF的进展，这些效果不能完全用阻断循环中的血管 紧张素II来解释。这是因为在长期应用ACEI治疗过程中，当循环中的ACE仍处于抑制状态时， 血管紧张素II的水平就开始下降，慢慢的恢复到以前水平。尽管ACE被抑制，但是已经引起了 所谓的血管紧张素II逃逸 这后来被证实由于旁路途径血管紧张素 I向血管紧张素II的转换引起所谓的血管紧张素II逃逸，这后来被证实由于旁路途径血管紧张素 I 向血管紧张素II的转换引起 。 Reference Biollaz J, et al. Antihypertensive therapy with MK 421: angiotensin II--renin relationships to evaluate efficacy of converting enzyme blockade. J Cardiovasc Pharmacol 1982;4(6):966- 972. •血管紧张素II的有害作用通过以下机制产生：刺激AT1受体，产生异常的血管收缩，刺激多种神经内分泌，促进生长，影响脉管系统，激活前血栓形成途径。 References Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355:637-645. Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin. Adv Intern Med. 2000;45:419- 429. MERIT-HF试验由各种死因绘成的Kaplan Meier死亡图表显MERIT HF试验由各种死因绘成的Kaplan Meier死亡图表显 示，由ER美托洛尔琥珀酸盐带来的益处出现的非常早，开始服 用后3个月就能显效，并且随着时间增长效果更明显。 与安慰剂组相比，ER美托洛尔琥珀酸盐治疗组的死亡率明 显下降。相对危险度下降34%。 • These major randomized, placebo-controlled trials studied the effect on survival of beta-blockade added to baseline therapy with ACE inhibition and diuretics in patients with HF. • CIBIS-II: The Cardiac Insufficiency Bisoprolol Study II enrolled 2647 patients with New York Heart Association (NYHA) class III–IV HF who were treatedwith New York Heart Association (NYHA) class III IV HF who were treated with bisoprolol, a β1-adrenergic receptor blocker.1 • MERIT-HF: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure enrolled 3991 patients with NYHA class II–IV HF who received treatment with metoprolol succinate CR/XL, a β1-adrenergic receptor blocker.2 • COPERNICUS: The Carvedilol Prospective Randomized Cumulative Survival Trial enrolled 2289 patients with NYHA class III–IV HF who received treatment with carvedilol, a β1-, β2-, α1-adrenergic receptor blocker.3 • The individual and pooled results of these studies show that beta-blockade consistently improves survival rates in patients with NYHA class II to l IV HFclass IV HF. 1. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet. 1999;353:9-13. 2. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007. 3. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344: 1651-1658. V-HeFT I Retrospective Analysis: Favorable Survival Trend in Black Patients • As evidenced by the Kaplan-Meier curves (right panel) from V-HeFT I, there was a 47% risk reduction in cumulative mortality over the duration of the trial in blacks treated with ISDN/HYD compared with those treated with placebo.1,2 • The left panel shows that on the contrary, there was no difference between the ISDN/HYD and the placebo-treated groups in white patients.1 • It should be noted that retrospective analyses are hypothesis generating only.1 References 1. Carson P, Ziesche S, Johnson G, Cohn JN, for the V-HeFT Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5:178-187. 2. NitroMed. Data on file. Patients in A-HeFT Were Maintained on Stable Background Therapies at Baseline • A high percentage of study participants were already receiving standard HF therapies such as diuretics, ß-blockers, ACE-Is, ARBs, digitalis glycosides, and aldosterone antagonists.1 • The values are slightly different in this table compared with those published in A-HeFT. This is because the analysis for A-HeFT included only the percentage of patients on background medications that were specifically reported as being givenpatients on background medications that were specifically reported as being given for HF; whereas, the information presented in the PI includes percent of patients on each background medication, including those for whom no use was specifically reported and those who were receiving therapy for non-HF−related reasons, eg, HTN.2 • Diuretics did not include aldosterone antagonists. References for notes 1. BiDil Prescribing Information. Lexington, Mass: NitroMed, Inc. August 2005. 2. NitroMed. Data on file. A-HeFT: Additional 43% Reduction in Mortality Beyond Current Standard Therapies • This Kaplan-Meier curve shows the 43% decrease in mortality among those patients treated with BiDil plus standard therapies. • This result led to the Data Safety and Monitoring Board’s recommendation to terminate the trial early. Reference BiDil Prescribing Information. Lexington, Mass: NitroMed, Inc. August 2005. A-HeFT: Additional 39% Risk Reduction in First Hospitalization for Heart Failure Beyond Current Standard Therapies • There was a significant decrease in the relative risk for first hospitalizations among patients treated with BiDil by 39%. • Separation between the two study arms appeared as early as 100 days. Reference BiDil Prescribing Information. Lexington, Mass: NitroMed, Inc. August 2005. • 当前的ACC/AHA 慢性心力衰竭指南强调心衰的每个阶段都与 治疗选择有关1,2。 • 阶段 A: 治疗应该包括减少危险因素以及患者和家属的教育。高 血压、血脂代谢紊乱和糖尿病应该定向治疗，ACEI或ARBs 应 该推荐给适合应用的患者。该推荐给适合应用的患者。 • 阶段 B: ACEI或ARBs 推荐给所有的患者；β-阻滞剂推荐给合 适的患者。 • 阶段 C: 所有的患者应该接受ACEI和β-阻滞剂的治疗。其它治 疗可能包括食用盐的限制，利尿剂和地高辛。 • –某些患者其它的治疗可以包括心脏再同步（如果存在束之 阻滞），血管成形术和二尖瓣外科手术，以及醛固酮拮抗剂和 奈西立肽。 • –一个多学科综合康复小组是非常有用的。 • 阶段 D: 顽固性症状需要特殊介入措施，包括强心剂, 辅助人工阶段 顽固性症状需要特殊介入措施，包括强心剂,辅助人 心脏 (VAD), 心脏移植和休养所。 1. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary: A report of the y p American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:2101-2113. 2. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007- 2018.