哈尔滨医科大学附属第二医院 心血管病医院 于波 CRT-D 在心衰患者猝死 防治中的价值 哈尔滨医科大学附属第二医院 心血管病医院 于波

心 衰 与 猝 死 预后比大多数肿瘤还要恶劣 1 World Health Statistics, World Health Organization, 1995. 2 American Heart Association, 2002 Heart and Stroke Statistical Update.

（2003年统计） ！ 21世纪的心血管流行病 — CHF and AF

美国SCA发病情况 335,000 SCA3 163,000 在美国，每年SCA 的发病人数超过所有这些疾病的总和 152,200 Stroke1 335,000 在美国，每年SCA 的发病人数超过所有这些疾病的总和 SCA3 Lung Cancer2 152,200 Breast Cancer2 SCA：心脏骤停 40,000 18,000 AIDS3 1 American Heart Association. Heart Disease and Stroke Statistics –2005 Update. 2 Jemel A. CA Cancer J Clin. 2003;53:5-26. 3 U.S. HIV & AIDS Statistic Summary. Avert.org.

目前美国 CHF 状况 约有 500万 CHF，每年新发病例约 55万 CHF是老年人最主要的心血管住院原因 尽管药物治疗取得显著进展，25%的心衰患者在诊断后2.5 年内死亡，其中50%为猝死（VT/VF） SCA一旦发生，存活率非常低（<1%），已成为严重的公众健康问题 1 American Heart Association. Heart Disease and Stroke Statistics – 2005 Update. 2 NHLBI, CHF Data Fact Sheet, September 1996. 3 Sweeney MO. PACE. 2001;24:871-888. 4 SOLVD Investigators. N Engl J Med 1992;327:685-691 5 SOLVD Investigators. N Engl J Med 1991;325:293-302. 6 Goldman S. Circulation 1993;87:V124-V131

！ 中国人口基数大，每年SCA的 发病人数超过54万

心衰病人心脏性猝死的危险性

心力衰竭和猝死 心衰的出现增加60-115%猝死 The proportionate contribution of SCD to total mortality in HF associated with reduced left ventricular function has not changed substantially between the Framingham data and now. Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212 在 Framingham 心脏研究39年的随访中, 无论男性还是女性，CHF 的出现明显增加心脏性猝死和全因死亡.1 1 Redrawn from Kannel WB, Wilson PWF, D'Agostino RB, Cobb J. Sudden coronary death in women. Am Heart J 1998 Aug; 136: 205-212

特殊人群SCD的发生率和年SCD发生人数 General adult population Multiple risk subgroups Patients with any previous coronary event Patients with ejection fraction <35% or CHF SCD-HeFT Cardiac arrest, VT/VF survivors AVID, CASH, CIDS Focusing on cardiac arrest survivors is NOT the answer because these patients represent only a very small percentage of the total number of patients who experience SCA each year. To address the greatest number of patients, primary prevention therapies will be required. Today, we can effectively identify/treat a very small portion of the total number of patients who experience SCA. SCD-HeFT may siginficantly increase our ability to treat high-risk heart failure patients. High-risk post-MI subgroups MADIT, MUSTT, MADIT II 5 10 20 25 30 100,000 200,000 300,000 Incidence of Sudden Deaths Per Year (number) Incidence of Sudden Death (% of group) Adapted from: Myerburg RJ. Sudden Cardiac Death: Exploring the Limits of Our Knowledge. J Cardiovasc Electrophysiol Vol. 12, pp. 369-381, March 2001.

LVEF与SCA的相关性 SCA危险性增加了6+ 倍 % SCA Victims LVEF 7.5% 5.1% 2.8% 1.4% 1 Gorgels, PMA Out-of-hospital cardiac arrest-the relevance of heart failure.The Maastricht Circulatory Arrest Registry.European Heart Journal.2003;24:1204-1209.

Control Group Mortality % CHF左室功能不全患者SCD的发生率 Control Group Mortality % References: CHF-STAT: Singh SN. N Engl J Med .1995;333:77-82. GESICA: Doval, HC. Lancet. 1994;344:493-498. SOLVD: Cooper H. Circulation. 1999;100:1311-1315. V-HEFT I: Goldman S. Circulation. 1993;87(6 Suppl):VI24-31 MERIT-HF Investigators. Lancet 1999;353:2001-2007. CIBIS II Investigators. Lancet:353:9-13. USCHFT. Packer M. N Engl J Med 1996; 334:1349-1355. 45 months 13 months 41.4 months 27 months 12 months 16 months 6 months 总死亡率 15-40%；SCD占总死亡的 50%.

在诊断为心衰的患者中，猝死的危险是普通人群的6－9倍 American Heart Association. Heart Disease and Stroke Statistics – 2005 Update.

心衰患者SCD的预防及治疗

尽管给予理想的药物治疗，心衰的猝死率仍非常高 1 MERIT-HF Study Group.Effect of metroprolol CR/XL in chronic heart failure.Lancet.1999;353:2001-2007. 2 CIBIS Investigations and Committees.The cardiac insufficiency bisprolol study II (CIBIS-II).Lancet.1999;353:9-13. 3 Packer M,Bristow MR,Cohn JN,et al.The effect of carvedilol on morbitity and nortality in patients with chronic heart failure.U.S.Carvedilol Heart Failure Study Group.N Engl J Med.1996;334:1349-1355. 4 The RALE Investigators.Effectiveness of spironolactone added to an aniotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure(the Randomized Aldactone Evaluation Study[RALES].Am J Cardiol.1997;78:902.

CRT治疗随机临床试验进展累计图

CRT与单纯药物治疗比较 在合理药物治疗的基础上, CRT治疗能显著减轻心衰症状，改善心功能和生活质量 可显著降低心衰病人全原因死亡率或主要心血管原因住院的联合终点达37% 可进一步降低心衰患者全原因死亡率达36% CRT治疗使心衰恶化死亡和猝死均有所下降，反映了心功能改善带来的益处

不同程度心衰的死亡原因 MERIT-HF研究死亡模式分析发现,NYHA II/III级患者的主要死因为SCA，而NYHA IV级的患者大多死于心衰 12% 26% 24% 59% 64% 15% 56% 33% NYHA Class II n = 103 NYHA Class III n = 103 11% NYHA Class IV n = 27 1 MERIT-HFStudy Group. Effect of Metoprolol CR/XL in chronic heart failure:Metoprolol CR/XL randomized intervention trial in congestive heart failure(MERIT-HF).LANCET. 1999;353:2001-2007.

心衰猝死的ICD治疗

MUSTT MI, EF<0.40, NSVT, &EP诱发VT 1 2 3 4 5 0.6 EP-指导的抗心律失常药物治疗 0.5 没有抗心律失常药物治疗 0.4 心律失常死亡和心脏骤停发生率 0.3 p < 0.001 EP-指导的ICD治疗 0.2 MUSTT was the next major primary prevention study that showed excellent results with ICD therapy. MUSTT was originally intended to compare EP-guided therapy (ICD or AAD) versus no antiarrhythmic therapy. On further analysis, the investigators found that ICD therapy was far superior to AAD drug therapy. The primary endpoint of MUSTT was arrhythmic mortality unlike all the other ICD trials which used overall mortality as the primary endpoint. The secondary endpoint in MUSTT was overall mortality. The entry criteria for MUSTT was similar to MADIT I: LVEF  40%, CAD, non-sustained VT, sustained VT on programmed electrical stimulation. Given the similar inclusion criteria, it is not surprising that the results of MUSTT were consistent with MADIT. After adjusting for covariates, MUSTT showed a 73% reduction in arrhythmic mortality and a 55% reduction in overall mortality in the ICD arm compared to patients taking no antiarrhythmic therapy. After the publishing of the MUSTT results, physician adoption of the MADIT indication increased significantly. This is not surprising given the consistent results and similar inclusion criteria of MADIT and MUSTT. 0.1 Time after Enrollment (Years) 与EP指导的抗性律失常药物治疗组和无抗心律失常药物治疗组相比，只有ICD能够明显降低死亡率 Buxton AE. N Engl J Med. 1999;341:1882-90. 20

MADIT-II MI> 4 周, LVEF < 30% 0.9 除颤器组 0.8 生存率 传统组2年死亡率25% 0.7 传统组 P = 0.007 0.6 By examining the Kaplan-Meier survival curves, we note that the ICD benefit began after approximately one year. Importantly, as demonstrated by the widening of the curves over time, the ICD benefit appears to increase over time. In an important recent analysis, Dr. Moss announced that there was a 40% cumulative probability of appropriate ICD therapy (ATP or shock) for VT or VF during the 4-year follow-up after ICD implantation. This finding clearly shows the improving cost-effectiveness of ICD therapy with longer follow-up periods.[i] [i] Moss, Arthur. MADIT I and MADIT II. Journal of Cardiovascular Electrophysiology. Vol. 14, No. 9, September 2003 0.0 1 2 3 4 No. At Risk 除颤器组 742 502 (0.91) 274 (0.94) 110 (0.78) 9 传统组 490 329 (0.90) 170 (0.78) 65 (0.69) 3 Year Moss AJ. N Engl J Med. 2002;346:877-83.

SCD-HeFT NYHA II/III(缺血或非缺血),LVEF≤35% 0.4 HR 97.5% Cl P-Value Amiodarone vs. Placebo 1.06 0.86, 1.30 0.529 ICD Therapy vs. Placebo 0.77 0.62, 0.96 0.007 0.3 Mortality 0.2 0.1 Amiodarone ICD Therapy Placebo 6 12 18 24 30 36 42 48 54 60 Months of follow-up

Hazard Ratio (95% CI) ICD vs. OMT Reduction in Death w/ICD DEFINITE试验 非缺血性DCM(LVEF<36%) 预防性 ICD治疗：n=454, 79% NYHA I-II Hazard Ratio (95% CI) ICD vs. OMT P-Value Reduction in Death w/ICD 全因死亡 (All Pts) 0.65 (0.40 - 1.06) 0.08 35% 全因死亡 (NYHA Class III) 0.37 (0.15 - 0.90) 0.02 63% 心律失常所致猝死 0.20 (0.06 - 0.71) 0.006 80%

CRT-D 在心衰猝死中的应用价值

主要研究终点：CRT和CRT－D均明显降低全原因死亡率 和全原因住院率的复合终点 2004年 COMPANION研究：CRT-D 治疗在不同年龄、不同性别、不同基础心脏病因、不同心功能分级、不同左心室射血分数、不同左心室舒张末径的心力衰竭患者获益的情况, 结论是处于不同情况的心力衰竭患者均能从CRT-D治疗中获益 。

二级终点：CRT可以降低全原因死亡率24%，P=0.059， CRT-D可降低36％，P=0.003

COMPANION 研究中死亡病例分析 313例死亡病人78%表现为心源性 ，最多见形式为泵功能衰竭 (44.4%) ，其次为SCD (26.5%) 与OPT相比，CRT-D显著地减少SCD(38%, p=0.006)，而单纯CRT减少SCD不明显(14.5%, p=0.33) CRT与CRT-D均有减少泵衰竭死亡的趋势 (29%, p = 0.11 and 27%, p=0.14) J Am Coll Cardiol. 2005 Dec 20;46(12):2329-34.

CARE-HF入选标准 >＝18岁 NYHA III/IV,需要襻利尿剂治疗的心衰至少持续6周 已接受标准药物治疗 LVEF=<35%, LVEDD>=30mm/m（除以身高参数) QRS>=120ms 如果患者QRS 在120ms与149ms之间，则需满足下列3条心脏收缩不同步标准中的两条： 主动脉射血前间期延迟>140ms 心室间机械延迟>40ms 左室后外侧壁激动延迟

一级终点 (所有原因死亡率或心血管住院率联合终点) 1.00 CRT : 159 pts (39%) 3 48 118 232 292 404 Medical Therapy 7 68 166 273 323 409 CRT Number at risk 500 1000 1500 0.00 0.25 0.50 0.75 HR 0.63 (95% CI 0.51 to 0.77) Event-free Survival Days P < .0001 Medical : 224 pts Therapy (55 %) Key Messages: The primary composite end-point (death or an unplanned hospitalization for a major cardiovascular event) was reduced substantially by CRT. There was no early hazard from device implantation. The curves began to separate within the first 90 days and remained separated during the follow up period. The absolute difference between the CRT and Medical Therapy arms in the percentage of patients reaching the primary endpoint during 29.5 months was 16%. 心脏再同步治疗与对照组相比使所有原因死亡率或心血管病因住院联合终点下降37%

CARE-HF Extension Study Time to Sudden Death 1.00 两年的随访中两条 曲线趋势一致 CRT 0.75 Medical Therapy Hazard Ratio 0.54 (95% CI 0.35 to 0.84; P=0.006) Survival 0.50 Main Study： CRT = 29 sudden deaths （7.1%） Medical Therapy = 38 sudden deaths (9.4%） CARE-HF also demonstrated, for the first time, that CRT also strikingly reduces the risk of sudden death. Indeed, sudden death dominated the clinical picture in the extension phase. This provides powerful evidence that CRT-induced improvements in cardiac function and efficiency also reduce the risk of sudden death. Potentially, many of the patients who died suddenly despite CRT might have survived had they received a CRT device with a defibrillator function (CRT-D). Further research is required to determine how best to select patients for CRT or CRT-D. 0.25 CRT = 32 sudden deaths (7.8%) Medical Therapy = 54 sudden deaths (13.4%) 0.00 400 800 1200 1600 Time (days) Main Study 平均随访时间：29.4m Extension Study 平均随访时间：37.6m

CRT及CRT-D临床研究进展 CARE-HF, COMPANION等研究进一步证明了CRT 在标准药物治疗的基础上，或较单纯的药物治疗能够降低死亡率和住院率，CRT-D能进一步降低高危患者的死亡率 COMPANION试验：CRT-D较CRT-P可以更进一步改善患者预后 CRT-D治疗可通过逆转重构，减少恶性室性心律失常的发生，减少ICD放电 CRT-D对猝死风险较大患者可以带来更大益处，是最佳治疗方案

目前认为，符合CRT适应证，同时又是猝死的高危人群，尤其是心肌梗死后或缺血性心肌病的心功能不良患者，应尽量植入CRT-D.

谢谢 谢谢！