慢性心力衰竭临床试验的回顾

1、心肌梗死心律失常猝死肌肉丢失神经激素激活重塑心室扩大心力衰竭死亡冠脉血栓心肌缺血CAD动脉硬化LVH危险因素 高脂蛋白血症 高血压 糖尿病 胰岛素抵抗Adapted from Dzau V. Braunwaid E.Am Heart J 1991:121:1244-1263 心肌受损心肌受损刺激交感刺激交感中枢性中枢性NE释放释放血管收缩血管收缩水潴水潴留留前负荷前负荷血管充血管充血血刺激血管加压素刺激血管加压素血浆血浆血管加压素血管加压素Adopted from Goldmith SR, Kubo SH, in Drug Treatment of Heart Failure, 1988; 5

2、0后负荷后负荷心肌功心肌功能能刺激肾素刺激肾素血浆血浆血管紧张素血管紧张素-II醛固酮醛固酮钠钠潴留潴留NE水平升高a b 受体兴奋细胞钙超载氧化应急心率心缩力及负荷增加心肌肥厚低血钾肾灌注压降低心肌细胞凋亡坏死心肌需氧增加心肌缺血心律失常肾素血管紧张素系统激活局部的血管紧张素 II分泌不依赖于血管紧张素转换酶血管紧张素原血管紧张素原肝脏肝脏血管紧张素血管紧张素I血管紧张素血管紧张素IIAT1AT2胃促胰酶胃促胰酶肾素肾素抑制剂抑制剂血管紧张素血管紧张素转换酶抑制剂转换酶抑制剂缬沙坦缬沙坦AT1受体拮抗剂受体拮抗剂缓激肽缓激肽羧氨酸羧氨酸血管收缩血管收缩血管增殖血管增殖醛固酮分泌醛固酮分泌心肌

3、细胞增殖心肌细胞增殖交感神经活性增加交感神经活性增加血管紧张素血管紧张素IIAT1AT2血管舒张血管舒张抗增殖抗增殖细胞凋亡细胞凋亡Myocardial InsultMyocardial DysfunctionRenin-Angiotensin-Aldosterone System Activation Sympathetic System ActivationReduced System Perfusion Altered Gene Expression Apoptosis RemodelingComplex cascadePathogenesis of Heart Failure急性心肌梗

4、死急性心肌梗死(数小时数小时)梗死扩张梗死扩张(数小时数天数小时数天)球型重塑球型重塑(数天数月数天数月)Ealapril (blinded)CIBIS-II Investigators and Committees, Lancet 1999;353:9-13CIBIS-II, Lancet 1999;353:9-13CIBIS-II, Lancet 1999;353:9-13Lancet 1999;353:2001-7050100150200250DeathCV DeathSudden DeathCHF Deathplacebo (n=2001)metoprolol CR/XL (n=199

5、0)Lancet 1999;353:2001-7Hjalmarson et al, JAMA 2000;283:1295-302 Hjalmarson et al, JAMA 2000;283:1295-302 Hjalmarson et al, JAMA 2000;283:1295-302 达利全显著降低轻中度慢性心衰病人的达利全显著降低轻中度慢性心衰病人的死亡率达死亡率达65%65%达利全达利全（n=696） 对照组对照组（n=398） 1.00.90.80.70.60.50 50 100 150 200 250 300 350 400 治疗时间治疗时间( (天天) )降低死亡危险降低死亡

6、危险 65% P0.001US Carvedilol Program生生存存率率达利全达利全(n=696)对照组对照组(n=398)050 100 150 200 250 300 350 4001.0 0.9 0.8 0.7 0.6 0.5p0.001Packer et al (1996)Lancet (1999)0 200 400 600 8001.00.80.60Bisoprolol对照组对照组p18岁岁; EF40%; NYHA IIIV906例死亡（记录事例死亡（记录事件）件）缬沙坦缬沙坦40 mg bid， 上上调至调至160 mg bid安慰剂安慰剂随机分随机分组组接受常规治疗包括

7、接受常规治疗包括ACE抑制剂、利尿剂、地高抑制剂、利尿剂、地高辛、辛、 b b- -阻滞剂阻滞剂（分层随（分层随机）机）OPTIMAAL OPtimal Trial In Myocardial infarction withthe Angiotensin II Antagonist Losartan 血管紧张素II拮抗剂氯沙坦心肌梗死最佳试验VALIANT VALsartan In Acute myocardial iNfarction Trial缬沙坦急性心肌梗死试验急性心梗急性心梗临床/放射学 心衰体征LVEF 65 mm新发Q波前壁心梗或 新发LBBB 或既往前壁Q波梗死再发心梗LVED

8、D:左室舒张末期内径LBBB:左束支传导阻滞随机分组(N=5,004)氯沙坦12.5 mg qd氯沙坦25 mg qd氯沙坦 50 mg qd卡托普利12.5 mg tid卡托普利25 mg tid卡托普利 50 mg tidDickstein K, Kjekshus J. Am J Cardiol 1999; 83(4):477-81. Dickstein K, et al. Lancet 2002; 360:752-60.急性心梗后高危患者死亡率30%30%20%20%10%10%10%10%卡托普利较好氯沙坦较好 ARB急需新的证据证实对高危心梗患者的疗急需新的证据证实对高危心梗患者的疗

9、效效左心室功能损害程度抗血小板药物-阻滞剂他汀类药物已证实疗效的ACE-I氯沙坦 50mg qd其他ARB?ACE-I + ARB?醛固酮拮抗剂LVSD 或急性心衰 LVSD 和急性心衰 Lancet. 2002;360:752760. Am J Cardiol. 1991;68:70D79D. Lancet. 1993;342:821828. N Engl J Med. 1995;333:16701676. Data on file. Novartis Pharmaceuticals. SAVEAIRETRACEOPTIMAALVALIANT2,2312,2311,9861,9861,749

10、1,7495,4775,4771414, ,7037030 02,0002,0004,0004,0006,0006,0008,0008,00010,00010,00016,00016,00012,00012,00014,00014,000评价心梗后患者心脏保护作用的大型研究 OPTIMAAL左心室功能不全左心室功能不全急性心衰急性心衰OPTIMAAL研究研究Captopril (4909)50mg tid4871 (99.2%)Vital status unknown:38 (0.8%)Median follow-up: 24.7 monthsValsartan (4909)160mg bid

11、4856 (98.9%)Vital status unknown:53 (1.1%)14 808 Patients Randomized4837 (99.0%)Vital status unknown:48 (1.0%)Combination (4885)50mg bid + 80mg bidInformed consent not ensured: 105 patientsVital status ascertained in 14 564 patients (99.05%)Vital status not ascertained in 139 patients (0.95%)14 703

12、Patients0.811.2危险比(97.5%可信区间)1.131.13P值(非劣效性)0.002方案治疗患者群体(n = 14,285)0.004意向治疗患者群体(n = 14,703)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非劣效性检验界值非劣效性检验非劣效性检验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TRACESAVEAIREVALIANT(归因分析)缬沙坦可保 留卡托普利99.6%的生存利益非劣效性成立缬沙坦优于卡托普利卡托普利优于缬

13、沙坦非劣效性不成立0.811.2危险比(97.5%可信区间)1.13P值(非劣效性)非劣效性 检验界值心血管死亡(1657例事件)0.001心血管死亡或心衰 (2661例事件)0.0001心血管死亡或心梗复发 (2234例事件)0.00001心血管死亡、心梗复发或心衰 (3096例事件)0.000001心血管死亡率和并发症率Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:18931906利于联合用药组利于卡托普利组平均年龄median血清肌酐medianmedianKillip分级 IIIIIIIV受体 No阻滞剂 Yes0

14、.512利于缬沙坦组利于卡托普利组#患者人数P值 0.512#患者人数P值 4618520067383080708827307564225456324182497048372718474716876190.960.550.930.120.710.670.844675511967683026708527097528226656424149490848782805467516556181.000.470.260.850.680.920.11290769110.48291068820.56亚组分析显示各亚组患者应用缬沙坦均受益亚组分析显示各亚组患者应用缬沙坦均受益缬沙坦 VS. 卡托普利:未服用 受

15、体阻滞剂 (n =2907) 服用 受体阻滞剂 (n =6911)联合用药 VS. 卡托普利:未服用 受体阻滞剂 (n =2910)服用 受体阻滞剂 (n =6882) 0.512利于卡托普利组利于缬沙坦组利于卡托普利组利于联合用药组0.560.48P值 (非劣效性)ARB可与可与阻滞剂阻滞剂和和ACEI安全地合用安全地合用Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349:18931906临床意义:VALIANT研究首次证实，ARB(缬沙坦)对心肌梗死后高危患者的治疗作用与ACEI相当.动脉粥样硬化动脉粥样硬化左室肥厚左室肥厚

16、重构重构心室扩张心室扩张充血性心衰充血性心衰终末期心脏病终末期心脏病危险因素危险因素 高血压高血压 吸烟吸烟 血脂水平血脂水平 糖尿病糖尿病 年龄年龄 等等死亡死亡1. Wolny et al. Circ Res 1997; 80(2): 219271.Ojima et al. Eur J Pharmacol 1997; 319: 13746. 2.Andersson et al. J Hum Hypertens 1997; 11(Supp2): S634.3.McKelvie et al. Circulation 1999; 100: 105664. 4.Granger et al. Am

17、Heart J 2000 139(4): 60917. 5.Riegger et al. Circulation 1999; 100: 222430. 6.Mitrovic et al. Am Heart J 2003; 145: E14. 1.McKelvie et al. Circulation 1999; 100: 1056642.Granger et al. Am Heart J 2000 139(4): 609173.Riegger et al. Circulation 1999; 100: 2224304.Mitrovic et al. Am Heart J 2003; 145:

18、E14ACE inhibitors, beta-blockers and spironolactone have been demonstrated to be life-saving in patients with CHFHowever, these patients still remain at high risk for cardiovascular death and recurrent hospital admissions for heart failure Angiotensin II type 1 (AT1) receptor blockers (ARBs) provide

19、 a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone systemARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor CHARM AddedCHARMPreserved3 com

20、ponent trials comparing candesartan to placebo in patients with symptomatic heart failureCHARMAlternativen=2028 LVEF 40%ACE inhibitor intolerantn=2548LVEF 40%ACE inhibitor treatedn=3025LVEF 40%ACE inhibitor treated/not treatedPrimary outcome for Overall Programme: All-cause deathPrimary outcome for

21、each trial: CV death or CHF hospitalisationMedian follow-up of 34 monthsCandesartann=1013Placebon=1015Completed Studyn=1011Completed Studyn=1014Lost to follow-upn=2Lost to follow-upn=12028 patients randomisedNYHA II-IV, LVEF 40%ACE inhibitor intolerant0123years01020304050PlaceboCandesartan%HR 0.77 (

22、95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p40%ACE inhibitor treated/not treatedCHARM AddedCHARMPreserved3 component trials comparingCandesartan to placeboCHARMAlternativen=2028 LVEF 40% ACE inhibitor intolerantn=2548LVEF 40%ACE inhibitor treatedPrimary outcome:CV death or CHF hospMedian follow-up

23、 of 41 monthsCandesartann=1276Placebon=1272Completed Studyn=1273Completed Studyn=1271Lost to follow-upn=3Lost to follow-upn=12548 patients randomisedNYHA II-IV, LVEF 40%ACE inhibitor treated0123years01020304050PlaceboCandesartanNumber at riskCandesartan127611761063948457Placebo1272113610139064223.5HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted H