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1、RAAS抑制剂的联合治疗 浙江大学心血管病研究所 浙江大学医学院附属第一医院 胡申江,ACE抑制剂和ARB：RAAS抑制,血管紧张素原,非-ACE 途径 (eg, chymase),血管收缩 细胞生长 Na/H2O 潴留 交感神经激活,肾素,血管紧张素 I,血管紧张素 II,ACE,咳嗽, 血管性水肿 益处?, 缓激肽,非活化片断,血管舒张 抗增殖 (激肽),醛固酮,AT2,AT1,ACE抑制剂,ARB,心脏保护的联合治疗证据,Val-HeFT VALIANT CHARM-Added ONTARGET,VALSARTAN HEART FAILURE TRIAL 缬沙坦治疗心力衰竭试验,心衰治疗
2、的里程碑,在主要心衰试验中生存率最高,National Vital Statistics Report. 1999; Cohn et al. NEJM 2001;345:1667; SOLVD Investigators. NEJM 1991;325:293; Cohn et al. NEJM 1986;12; Packer M, et al. NEJM 1996; Consensus Study Group NEJM 1987; Packer M, et al. NEJM 1991;325:1468,研究回顾,代文 降低所有原因病死率与发病率联合终点13.2%,Cohn JN. Circul
3、ation. 2000;102:2672-2676.,0,65,70,75,80,85,90,95,缬沙坦,安慰剂,100,* p=0.009,月,无事件概率 (%),代文 降低心力衰竭住院*27.5%,0,65,70,75,80,85,90,95,100,* p0.00001,月,无事件概率,*First hospitalization.Cohn JN. Circulation. 2000;102:2672-2676.,缬沙坦,安慰剂,27.5% 危险降低*,代文降低所有原因病死率和病残率联合终点44%,未接受ACEI基础治疗亚组,* p0.00002,月,无事件生存率,Maggioni A
4、P, Anand IS et al. JACC,2002),缬沙坦 n = 185,安慰剂 n = 181,44% 危险降低*,50,100,0,3,6,9,12,15,18,21,24,27,30,生存率 (%),60,70,80,90,随机分组后 (月),* P = 0.017,代文降低所有原因死亡率33%,Maggioni AP, Anand IS et al. JACC,2002),缬沙坦 n = 185,安慰剂 n = 181,未接受ACEI基础治疗亚组,33% 危险降低*,主要终点: 总死亡率次要终点: 心血管死亡、心肌梗死、心力衰竭其他终点: 安全性和耐受性,卡托普利 50mg
5、tid(n = 4909),缬沙坦 160mg bid(n = 4909),卡托普利 50mg tid +缬沙坦 80mg bid (n = 4885),急性心肌梗死(0.510天)符合SAVE、AIRE或者TRACE研究的入选标准 (具备心力衰竭的临床/放射影象学证据和/或左室收缩功能障碍),随机、双盲、活性对照,平均随访时间:24.7月 事件驱动,VALIANT研究设计,Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349,缬沙坦+卡托普利 VS. 卡托普利: 危险比 =0.98； P = 0.726,卡托普利,0,0.05,
6、0.1,0.15,0.2,0.25,0.3,0,6,12,18,24,30,36,月,缬沙坦 VS. 卡托普利: 危险比 = 1.00； P = 0.982,VALIANT研究主要终点：总死亡率,总死亡率,代文可降低心肌梗死高危患者死亡率达25%,死亡率危险比,利于有效药物,利于安慰剂,Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349,三项研究的联合死亡率,缬沙坦可保 留卡托普利99.6%的 生存利益,25%,非劣效性成立,缬沙坦优于卡托普利,卡托普利优于缬沙坦,非劣效性不成立,缬沙坦降低心血管死亡 和主要心血管事件危险与AC
7、EI相当,0.8,1,1.2,危险比 (97.5%可信区间),1.13,P值 (非劣效性),非劣效性检验界值,心血管死亡率和并发症率,卡托普利(n=4,909),VALIANT：急性心梗后缬沙坦、 卡托普利或两者对动脉粥样硬化事件的作用,缬沙坦 (n=4,909),缬沙坦 + 卡托普利(n=4,885),25 20 15 10 5 0,至少发生一例事件的患者 (%),心肌梗死 心绞痛 血管重建 卒中,Adapted from McMurray et al. Presented at ESC 2005,0,0.1,0.2,0.3,0.4,0,6,12,18,24,30,36,月,事件概率,缬沙坦
8、中止治疗的发生率显著低于卡托普利,所有原因中止,不良事件中止,*p0.05 vs 卡托普利,*,*,CHARM-Added: Study design,McMurray JJV et al. Lancet. 2003;362:761-71.,Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added,Randomized, double-blind NYHA class IIIV, LVEF 40%, stable ACEI dose for 30 days N =
9、 2548,Candesartan 32 mg qd n = 1276,Placebo n = 1272,Median follow-up: 41 months,Primary outcome: CV death or hospitalization for HF,ACEI = angiotensin-converting enzyme inhibitor,CHARM-Added: Baseline characteristics by ACEI dose,McMurray JJV et al. Am Heart J. 2006;151:985-91.,CHARM-Added: Daily A
10、CEI dose,McMurray JJV et al. Am Heart J. 2006;151:985-91.,*Based on European Society of Cardiology guidelines Not indicated for heart failure,Subgroup analysis, most commonly used ACEIs,Recommended (CHARM prespecified)* (n = 1291),Maximum (FDA) (n = 529),All patients (N = 2548),CHARM-Added: Primary
11、outcome of CV death or HF hospitalization,N = 2548,McMurray JJV et al. Am Heart J. 2006;151:985-91.,Recommended dose of ACEICHARM prespecified Maximum dose of ACEI FDA 2005 CHARM-Added CHARM-Alternative Pooled results (low LVEF patients),No Yes No Yes,1257 1291 2019 529 2548 2028 4576,0.260.29,Patie
12、nts (n),Candesartan better,Placebo better,P value for interaction,0.6,0.8,1,1.2,Hazard ratio (95% Cl),CHARM-Added: Primary outcome in patients taking a -blocker,McMurray JJV et al. Am Heart J. 2006;151:985-91.,n = 1413,CV death or HF hospitalizationRecommended dose of ACEICHARM prespecifiedMaximum d
13、ose of ACEIFDA 2005All patients,No Yes No Yes,692 721 1100 3131413,0.690.64,Patients (n),Candesartan better,Placebo better,P value for interaction,0.6,0.8,1,1.2,Hazard ratio (95% Cl),Summary: CHARM-Added,Candesartan reduced CV death or HF hospitalization in patients taking no ACEI, a moderate ACEI d
14、ose, or a high ACEI dose Benefits of candesartan in HF patients were not modified by either ACEI dose or concomitant therapy with a -blocker ACEIs and angiotensin receptor blockers (ARBs) have distinct and complementary mechanisms of action Combined use of an ACEI and the ARB, candesartan, improved
15、outcomes in patients with HF vs ACE inhibition alone,McMurray JJV et al. Am Heart J. 2006;151:985-91.,ARBs 治疗心肌梗死和心力衰竭: 现今的观点,Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8., 抗血小板药物 -阻滞剂(冠心病) 他汀类 ACE抑制剂,心血管高危人群基础药物治疗,疑问：替米沙坦(ARB) “不劣于”雷米普利(ACEI)? 联合用药优于单用雷米普利? 终点事件：主要终点：CV死亡、MI、卒中、CHF住院关键的次要终点：CV死亡、MI、卒中(HOPE试验的终点) 研究设计： 单盲入组(n=29,019) 在40个国家的733个中心(n=25,620)进行的随机、双盲、双模拟研究 随访56个月，确认99.8%的终点事件,ONTARGET 试验,主要的基线特征,ONTARGET,与基线相比血压变化,与雷米普利组相比，联合治疗组血压进一步下降2.4/1.4mmHg，替米沙坦组进一步下降0.9/0.6mmHg,
