该研究组招募了4822名纽约心脏协会（NYHA）II-IV级的心力衰竭、射血分数45%及以上、钠尿肽水平升高和结构性心脏病的患者，并随机分配接受Sacubitril+缬沙坦治疗或单独缬沙坦治疗。

Sacubitril-缬沙坦组有526例患者因心力衰竭和心血管死亡共住院894次，缬沙坦组有557例患者共住院1009次，风险比为0.87。Sacubitril–缬沙坦组和缬沙坦组的心血管死亡率分别为8.5%和8.9%，风险比为0.95；因心力衰竭住院的总人次分别为690和797人，风险比为0.85。Sacubitril–缬沙坦组中15.0%的患者NYHA分级改善，显著高于缬沙坦组（12.6%），优势比为1.45；肾功能恶化率为1.4%，显著低于缬沙坦组（2.7%），风险比为0.50。

8个月时，Sacubitril–缬沙坦组堪萨斯城心肌病调查问卷（KCCQ）的临床总结评分平均高了1.0分。Sacubitril–缬沙坦组患者低血压和血管水肿的发生率较高，高钾血症的发生率较低。在12个预先指定的亚组中，有迹象表明射血分数较低的患者和妇女可获益于Sacubitril–缬沙坦。

综上，Sacubitril–缬沙坦治疗心力衰竭和射血分数45%及以上的患者未能显著降低心力衰竭和心血管死亡的总住院率。

据悉，在心力衰竭和射血分数降低的患者中，血管紧张素受体-脑啡肽酶抑制剂Sacubitril+缬沙坦降低了因心力衰竭或心血管死亡而住院的风险。对于射血分数保留型的心力衰竭患者，血管紧张素受体-脑啡肽酶抑制剂的作用尚不清楚。

BACKGROUND
The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor–neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear.

METHODS
We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed.

RESULTS
There were 894 primary events in 526 patients in the sacubitril–valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril–valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril–valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril–valsartan group. Patients in the sacubitril–valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril–valsartan in patients with lower ejection fraction and in women.

CONCLUSIONS
Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.)