射血分数对沙库巴曲缬沙坦（LCZ696）治疗射血分数降低的心力衰竭的疗效及预后的影响：ARNI与ACEI对心力衰竭全球死亡率和发病率影响的前瞻性比较（PARADIGM-HF）试验

Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial.

作者信息

Solomon Scott D, Claggett Brian, Desai Akshay S, Packer Milton, Zile Michael, Swedberg Karl, Rouleau Jean L, Shi Victor C, Starling Randall C, Kozan Ömer, Dukat Andrej, Lefkowitz Martin P, McMurray John J V

机构信息

From the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., B.C., A.S.D.); Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.Z.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); National Hearth and Lung Institute, Imperial College, London, UK (K.S.); Institut de Cardiologie de Montreal, Université de Montreal Canada (J.L.R.); Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Dokuz Eylül University Medicine Faculty Izmir, Turkey (O.K.); Second Department of Internal Medicine, Comenius University, Bratislava, Slovakia (A.D.); Novartis, East Hanover, NJ (V.C.S., M.P.L.); BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M.).

出版信息

Circ Heart Fail. 2016 Mar;9(3):e002744. doi: 10.1161/CIRCHEARTFAILURE.115.002744.

DOI:10.1161/CIRCHEARTFAILURE.115.002744

PMID:26915374

Abstract

BACKGROUND

The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril.

METHODS AND RESULTS

Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95).

CONCLUSIONS

In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

摘要

背景

在心力衰竭（HF）且射血分数降低（EF）的患者中，与依那普利相比，血管紧张素受体脑啡肽酶抑制剂沙库巴曲/缬沙坦（LCZ696）降低了心血管疾病的发病率和死亡率。在“血管紧张素受体脑啡肽酶抑制剂与血管紧张素转换酶抑制剂对心力衰竭全球死亡率和发病率影响的前瞻性比较”（PARADIGM-HF）试验中，沙库巴曲/缬沙坦降低了射血分数。我们评估了EF对临床结局以及与依那普利相比沙库巴曲/缬沙坦有效性的影响。

方法与结果

8399例纽约心脏协会II至IV级HF且EF降低[左心室EF（LVEF）≤40%]的患者被随机分为每日两次服用97/103mg沙库巴曲/缬沙坦组和每日两次服用10mg依那普利组，中位随访27个月。主要研究终点为心血管死亡或HF住院。在各研究点评估LVEF并记录在病例报告表上。我们将LVEF与研究结局相关联，并评估沙库巴曲/缬沙坦在整个LVEF范围内的有效性。各研究点报告的PARADIGM-HF试验中的平均LVEF为29.5（四分位间距，25-34）。所有结局的风险均随LVEF降低而增加。LVEF每降低5个百分点，心血管死亡或HF住院风险增加9%（风险比，1.09；95%置信区间，1.05-1.13；P<0.001），心血管死亡风险增加9%（风险比，1.09；95%置信区间，1.04-1.14），HF住院风险增加9%（风险比，1.09；95%置信区间，1.04-1.14），全因死亡率风险增加7%（风险比，1.07；95%置信区间，1.03-1.12）（校正分析）。当按三分位数（P交互作用=0.87）或连续变量（P交互作用=0.95）进行建模时，沙库巴曲/缬沙坦在整个LVEF范围内均有效，且无异质性证据。