Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D.S., M.V., B.L.C., M.A.P., A.D.).
Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
Circulation. 2020 Feb 4;141(5):352-361. doi: 10.1161/CIRCULATIONAHA.119.044586. Epub 2019 Nov 17.
While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone-system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF.
We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF.
Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone-system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78-0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76-0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77-0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81-0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions.
The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone-system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men.
https://www.clinicaltrials.gov. Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).
虽然有治疗心力衰竭（HF）伴左心室射血分数（LVEF）降低的疾病修正疗法，但对于 LVEF 较高（>40%）的患者，可用的选择很少。沙库巴曲缬沙坦已在两项同样设计的射血分数降低和保留的心力衰竭患者临床试验中与肾素-血管紧张素-醛固酮系统抑制剂进行了比较，允许在整个 LVEF 范围内检查其效果。
我们在预先指定的汇总分析中合并了 PARADIGM-HF（LVEF 入选标准≤40%；n=8399）和 PARAGON-HF（LVEF 入选标准≥45%；n=4796）的数据。我们将随机分组的患者分为 LVEF 类别：≤22.5%（n=1269），>22.5%至 32.5%（n=3987），>32.5%至 42.5%（n=3143），>42.5%至 52.5%（n=1427），>52.5%至 62.5%（n=2166），和>62.5%（n=1202）。我们评估了首次心血管死亡和 HF 住院的时间、其组成部分以及总 HF 住院、全因死亡率和非心血管死亡率。在 LVEF 各个类别中，我们检查了发病率和治疗效果。
在 13195 名随机患者中，我们观察到在最高组与最低组之间，心血管死亡和 HF 住院的发生率较低，但非心血管死亡的发生率相似。总体而言，沙库巴曲缬沙坦优于肾素-血管紧张素-醛固酮系统抑制剂，用于首次心血管死亡或心力衰竭住院（风险比 [HR] 0.84 [95%置信区间，0.78-0.90]），心血管死亡（HR 0.84 [95%置信区间，0.76-0.92]），HF 住院（HR 0.84 [95%置信区间，0.77-0.91]）和全因死亡率（HR 0.88 [95%置信区间，0.81-0.96]）。沙库巴曲缬沙坦的效果受 LVEF 影响（治疗与连续 LVEF 交互作用=0.02），并且似乎在 EF 主要低于正常范围的个体中存在获益，尽管心血管死亡的治疗获益在射血分数较低时会降低。我们观察到沙库巴曲缬沙坦在男性和女性中对复合总 HF 住院和心血管死亡的疗效存在 LVEF 效应修饰，尽管女性在较高的射血分数下获益。
与单独使用肾素-血管紧张素-醛固酮系统抑制剂相比，沙库巴曲缬沙坦的治疗效果因 LVEF 而异，治疗获益，特别是心力衰竭住院，似乎延伸至射血分数轻度降低的心力衰竭患者。与男性相比，这些治疗益处似乎在女性中扩展到更高的 LVEF 范围。
https://www.clinicaltrials.gov。唯一标识符：NCT01920711（PARAGON-HF），NCT01035255（PARADIGM-HF）。
