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血管紧张素-脑啡肽酶抑制剂与依那普利治疗心力衰竭的疗效比较
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure


John J.V. McMurray ... 心脑血管疾病 • 2014.09.11
相关阅读
• 血管紧张素脑啡肽酶抑制疗法治疗射血分数保留的心力衰竭 • 关于心力衰竭管理方案的重点更新

摘要


背景

在射血分数降低的心力衰竭患者中,我们比较了血管紧张素受体-脑啡肽酶抑制剂LCZ696和依那普利的疗效。在既往研究中,依那普利改善了此类患者的生存率。

 

方法

在这项双盲试验中,我们纳入了8,442例心功能为Ⅱ、Ⅲ或Ⅳ级且射血分数≤40%的心力衰竭患者,这些患者在接受推荐治疗的基础上被随机分配接受LCZ696(200 mg,每天2次)或依那普利(10 mg,每天2次)治疗。主要结局为由心血管原因死亡或心力衰竭住院组成的复合终点,但这项试验旨在检测心血管原因所致死亡率的差异。

 

结果

根据预先设定的规则,在中位随访27个月后,这项试验被提前终止,因为LCZ696的极大益处已超越了界值。试验结束时,LCZ696组有914例患者(21.8%)发生了主要结局,依那普利组有1,117例患者(26.5%)发生了主要结局(LCZ696组的风险比为0.80,95%可信区间[CI]为0.73~0.87,P<0.001)。共有711例(17.0%)接受LCZ696的患者以及835例(19.8%)接受依那普利的患者死亡(任何原因死亡的风险比为0.84,95% CI为0.76~0.93,P<0.001),在这些患者中,心血管原因死亡患者数分别为558例(13.3%)和693例(16.5%)(风险比为0.80,95% CI为0.71~0.89,P<0.001)。与依那普利相比,LCZ696还使心力衰竭住院的危险降低了21%  (P<0.001),并且减少了心力衰竭的症状和体力限制(P=0.001)。LCZ696组有低血压和非严重血管性水肿的患者比例高于依那普利组,但肾损害、高钾血症和咳嗽的患者比例低于依那普利组。

 

结论

LCZ696在降低心力衰竭死亡危险和住院率方面优于依那普利(由诺华公司[Norvatis]资助;PARADIGM-HF研究在ClinicalTrials.gov注册号为NCT01035255)。





作者信息

John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees*
From the British Heart Foundation (BHF) Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.); the Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.); the Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston (A.S.D., S.D.S.); Novartis Pharmaceuticals, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de Montréal, Montreal (J.L.R.); the Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College London, London (K.S.); and the Medical University of South Carolina and Ralph H. Johnson Veterans Affairs Medical Center, Charleston (M.R.Z.). Address reprint requests to Dr. Packer at the Department of Clinical Sciences, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, or atmilton.packer@utsouthwestern.edu; or to Dr. McMurray at the BHF Cardiovascular Research Centre, University Pl., University of Glasgow, Glasgow, Scotland G12 8QQ, United Kingdom, or atjohn.mcmurray@glasgow.ac.uk. *A complete list of the investigators in the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. The 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

2. The 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

3. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004;110:2618-2626

4. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675

5. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-1658

6. 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

7. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13

8. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717

9. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21

10. Cruden NL, Fox KA, Ludlam CA, Johnston NR, Newby DE. Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension 2004;44:913-918

11. Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci (Lond) 1996;91:283-291

12. Wilkinson IB, McEniery CM, Bongaerts KH, MacCallum H, Webb DJ, Cockcroft JR. Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP). Br J Clin Pharmacol 2001;52:159-164

13. Maric C, Zheng W, Walther T. Interactions between angiotensin ll and atrial natriuretic peptide in renomedullary interstitial cells: the role of neutral endopeptidase. Nephron Physiol 2006;103:149-156

14. Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 2004;99:76-82

15. Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol 1998;31:116-125

16. Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad MM. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol 1999;34:782-790

17. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-111

18. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920-926

19. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010;50:401-414

20. Hegde LG, Yu C, Renner T, et al. Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat. J Cardiovasc Pharmacol 2011;57:495-504

21. Ruilope LM, Dukat A, Bohm M, Lacourciere Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet 2010;375:1255-1266

22. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387-1395

23. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062-1073

24. McMurray JJ, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2014;16:817-825

25. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35:1245-1255

26. Maggioni AP, Anker SD, Dahlstrom U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2013;15:1173-1184

27. Fryer RM, Segreti J, Banfor PN, et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol 2008;153:947-955

28. Fonarow GC, Albert NM, Curtis AB, et al. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF). Circulation 2010;122:585-596

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