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MADIT II 8 年随访结果启示

MADIT II 8 年随访结果启示. 兰州大学第一医院 张 钲. 关于 MADIT. 过去 15 年在临床研究上的大力投入证实了装置治疗的有效性. MIRACLE (ICD). PreSCD II (ICD). BSC 赞助的研究. ~. PACMAN (CRT). DEFINITE (ICD). RHYTHM (ICD). CRediT (ICD, CRT). MADIT 系列研究. ~. COMPANION (CRT-P and -D). PreSCD I (ICD).

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MADIT II 8 年随访结果启示

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  1. MADIT II 8年随访结果启示 兰州大学第一医院 张 钲

  2. 关于 MADIT ...

  3. 过去15年在临床研究上的大力投入证实了装置治疗的有效性过去15年在临床研究上的大力投入证实了装置治疗的有效性 MIRACLE (ICD) PreSCD II (ICD) BSC 赞助的研究 ~ PACMAN (CRT) DEFINITE (ICD) RHYTHM (ICD) CRediT (ICD, CRT) MADIT 系列研究 ~ COMPANION (CRT-P and -D) PreSCD I (ICD) MADIT II 8 Yr Follow-Up MADIT II(ICD, primary prevention) AVID (ICD, secondary prevention) CIDS (ICD, secondary prevention) PATH-CHF 1 (CRT) CONTAK CD (CRT-D) SCD-HeFT (ICD) MADIT-CRT (CRT-D) MADIT(ICD, primary prevention) CABG-Patch (ICD, primary prevention) MUSTT(ICD, primary prevention) CASH(ICD) CAT(ICD, primary prevention) PATH-CHF II (CRT-P and -D) CARE-HF (CRT) REVERSE (CRT) 2009/10 2006/7/8 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 通往指南之路 ACC/AHA Guidelinesfor ICDs ACC/AHA/ESC Updated Guidelines ESC HF focused Guidelines update ESC Updated Guidelines Dates are publication dates 3

  4. 尽管有明确的临床证据和指南，还是有约90％的患者未能接受ICD治疗尽管有明确的临床证据和指南，还是有约90％的患者未能接受ICD治疗 欧洲符合 ICD/CRT-D指征的患者 700,000 在欧洲的实际植入量 600,000 500,000 植入数量 400,000 300,000 200,000 70,000 100,000 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 0% MADIT MUSTT MADIT II COMPANION SCD-HeFT MADIT-CRT AVID CASH 4 Source: Eucomed CRM data, Internal estimates based on most recent ESC Guidelines and S.Nisam pub.

  5. MADIT II 8年随访结果能改变局面吗? “这是第一次有长期研究数据能证实ICD可以挽救心脏性猝死一级预防患者的生命”. Ilan Goldenberg, MD, University of Medicine - Rochester, Principal investigator of MADIT II 8-Year FU “MADIT-II研究长期随访结果为在美国和其他国家排位死亡率第一位即心脏性猝死的高危患者带来了长期生存的希望。 此项研究证明ICD在挽救生命上的持续有效性，至少8年的长期随访结果证实ＩＣＤ能增加生存的获益性 .”

  6. MADIT II 8年随访的公开数据Dr Ilan Goldenberg主要研究者

  7. LONG-TERM BENEFIT OF PRIMARY PREVENTION WITH AN IMPLANTABLE CARDIOVERTER DEFIBRILLATOR植入型除颤器对猝死一级预防的长期意义 An Eight Year Follow-Up Study of the Multicenter Automatic Defibrillator Trial II Ilan Goldenberg M.D., John Gillespie M.D., Arthur J. Moss M.D., W. Jackson Hall Ph.D., Helmut Klein M.D., Scott McNitt M.S., Mary W. Brown M.A., Iwona Cygankiewicz M.D., Wojciech Zareba M.D., and the executive committee of the Multicenter Automatic Defibrillator Implantation Trial-II* From the Cardiology Unit of the Department of Medicine (IG, AJM, HK, SM, MB, IC, WZ) the Department of Biostatistics and Computational Biology (WJH), University of Rochester Medical Center, Rochester, N.Y, and the University of Buffalo, Buffalo, NY (JG). Sponsored by Boston Scientific Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  8. 情况介绍: 当前 ICD一级预防指南 I 类适应证 • EF ≤ 35% n=196 CAD, EF ≤ 0.35, NSVT, EP+ MADIT 0.46 1996 n=900 CABG, EF ≤ 0.35, SAECG+ CABG-Patch 1.07 ESC 2008 指南 1997 • 建立在短期研究数据上 n=1232 CAD & EF ≤ 0.30 MADIT II 0.69 2002 n=903 ICM & NICM, NYHA III/IV, EF ≤ 0.35, QRS ≥ 0.12 COMPANION 0.64 2004 n=458 NICM, EF ≤ 0.35, PVC or NSVT DEFINITE 0.65 2004 n=1676 ICM & NICM, NYHA II/III, EF ≤ 0.35 SCD-HeFT 0.77 2004 n=674 Acute MI, EF ≤ 0.35, HRV DINAMIT 1.08 2004 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 传统治疗更优 ICD 更优 迄今，没有关于ICD治疗长期有效性的数据，也无该类足以支持到超过ICD使用年限数据。 + MADIT: Moss AJ, et al:. N Engl. J Med 1996, 335:1933-1940 , CABG-Patch: Bigger et al. N Engl J Med 1997;337:1569-75, MADIT-II: Moss et al. New Engl J Med. 2002; 346 (12): 877, COMPANION: Bristow MR et al. N Engl J Med. 2004;350:2140-2150, DEFINITE: Levine et al, N Engl J Med 2004;350:2151-58, SCD-HeFT: Bardy et al. New Engl J Med. 352 (3): 225 ,. DINAMIT: Hohnloser S et al., N Engl J Med 2004;351:2481-88,

  9. MADIT II • 1232 心梗后患者: • EF ≤ 30% • NYHA I – II – III • 平均随访: • 20 个月 • 结果: • HR = 0.69 (p=0.016) • 0.17 挽救生命年数 1.0 0.9 Defibrillator 0.8 Probability of Survival 0.7 传统治疗 0.6 HR=0.69 P=0.016 0.0 0 1 2 3 4 Years 患者人数 除颤器 传统治疗 0.17 ICD为有心梗史和EF ≤ 30%的患者提供了显著的生存获益性证据–但该生存获益性是否能持续并延长到8年随访时? + Moss AJ et al., N Engl J Med. 2002; 346: 877-883

  10. 研究目的 • 评价MADIT II患者随访至8年时ICD治疗对一级预防患者的益处 Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  11. 数据采集 • 在预审中的数据 • MADIT II: 07/1997 – 11/2001 • 基于以下条件的所有数据跟踪到2009年3月: • 在U.S. 的中心 (n=1123): 国家死亡档案 • 非U.S. 的中心 (n=109): 死亡档案 / 医院 Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  12. 研究目的: 有效性分析 • 记录所有在研究中患者的交叉治疗数据 • 在预审时: • 未植入ICD 转为植入ICD: 27 名患者 • ICD治疗转为非ICD治疗: 13 名患者 (ICD removal) • 研究后: • 非ICD转为ICD治疗: 140 名患者 所有在研究中患者的交叉治疗数据都予以记录直到随访研究结束 + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  13. MADIT II: 起搏情况 Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  14. 观察结果 • 主要终点分析 • 入选后8年的全因死亡率 • 次要终点分析 • 早期 ICD 得益 (0-4 年) 与 后期 ICD 得益 (5-8 年)的比较 • 装置类型 (单双腔 ICD比较) • 心衰 (HF)对ICD治疗长期益性的影响 Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  15. 统计分析 • Cox比例风险回归模型: • 时间依赖性模式: 多元Cox-模型治疗组和起搏类型的时间相关协变量 • 意向治疗分析: 根据原始数据随机分配的多元Cox模型治疗 • 分析报告 • 应用Kaplan-Meier • 对随访期间治疗变化的监察 (= 交叉) Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  16. 治疗组长期死亡率: Kaplan-Meier (有效性分析) 8 年随访时 （F-U） 0.7 Unadjusted p < 0.001 0.62 • 8年时累积全因死亡率: • 非ICD组: 62% • ICD组: 49% 0.6 ARR=13% RRR=34% 0.5 Non-ICD 0.49 0.4 Cumulative Probability of Mortality ICD 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 Years 8年随访结果显示ICD治疗组和非ICD治疗组相比显著降低了累积全因死亡率 + + + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  17. 不同时间段的生存差异: *NNT=1/ARR 8年随访时的生存差异相当于ICD治疗的生命挽救年增加为0.52且NNT从17减少到 8 + + + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  18. 多变量分析:*植入与未植入ICD患者的长期死亡率风险比较多变量分析:*植入与未植入ICD患者的长期死亡率风险比较 持续观察8年，结果显示对死亡率影响为：植入ICD的患者在4年时相对死亡率降低39％，在8年时降低34％。 + + * Adjusted for age, gender, NYHA class, BUN, EF, QRS duration; therapy group assessed as a time-dependent covariate Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  19. 各亚组患者ICD治疗的长期获益性比较 生存获益性在亚组分析时能保持一致性 + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  20. 研究后分析:*心衰患者的获益 研究期间未出现心衰的患者获益更大 + * Among patients who survived to trial closure; Adjusted for age, gender, BUN, EF, QRS duration Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  21. 起搏类型与长期死亡率 0.7 Unadjusted p < 0.001 • 单腔 ICD • 8年时死亡率持续下降 • 双腔装置 • 后期死亡率增加 0.6 0.5 Non-ICD Dual-ICD 0.4 Cumulative Probability of Mortality 0.3 Single-ICD 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 Years 双腔ICD和心室频繁起搏患者显示更高死亡率，而单腔ICD植入者和极少起搏患者获益增加 + + + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  22. 研究后分析:*起搏类型的获益性 * Among patients who survived to trial closure; Adjusted for age, gender, BUN, EF, QRS duration, HF status at trial closure Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  23. 结论 + 短期 ICD 治疗可获益的结果可以持续到 8-年随访时 + 后期获益 (死亡率降低)因素 • 低RV 起搏比例 • 后期未受心衰的影响 Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271.

  24. MADIT II患者长期ICD治疗的成本效益 MADIT II 人群 (3.5 年随访时平均随访 2- 年) MADIT II 人群长期模拟 预测数据* MADIT II 人群 8年随访时 HR: 0.66 HR:0.68 HR:0.69 ICER = 未计算但根据模拟分析法得出将进一步改善的结论 ICER = $ 60 000 – 80 000 ICER = $ 235 000 *Zwanziger J, Hall WJ, Dick AW, Zhao H, Mushlin AI, Hahn RM, Wang H, Andrews ML, Mooney C, Wang H, Moss AJ.The cost effectiveness of implantable cardioverter-defibrillators: results from the Multicenter automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol. 2006;47:2310- 2318. + Goldenberg I et al., Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator. Circulation 2010; 122:1265-1271. 预计的边际成本效益比 (ICER)

  25. Thank you for your attention

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