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Superior Clinical Outcomes Seen in HFrEF With Early Initiation of Sacubitril/Valsartan


Two periods of sacubitril/valsartan initiation were compared in a study population of patients with heart failure with reduced ejection fraction (HFrEF): less than 3 months or 3 or more months following first HFrEF diagnosis.

Patients with de novo heart failure with reduced ejection fraction (HFrEF) who initiated treatment with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Sac/Val) less than 3 months after receiving their HFrEF diagnosis had superior clinical outcomes and earlier left ventricular (LV) reverse remodeling vs Sac/Val therapy that began 3 or more months after initial diagnosis.

De novo HF is sudden onset of acute HF with no prior history of heart disease.

Findings were recently published in ESC Heart Failure.

Two major studies—PARADIGM-HF and PIONEER-HF—along with other previous research bear out the benefits of treatment with Sac/Val compared with other regimens, particularly angiotensin converting enzyme inhibitors. “However, the clinical benefits of earlier use of Sac/Val vs later use of Sac/Val after discharge have not been well established,” wrote the study investigators, whose primary outcome was HF hospitalization and cardiac-related death, and secondary outcomes were all-cause death, cardiac death, ventricular tachycardia or fibrillation, cardiac reverse remodeling, EF change, HF hospitalization, and readmission before or after Sac/Val use.

Their retrospective analysis encompassed 115 patients with documented Sac/Val use between June 2017 and October 2019 and the 2 treatment initiation periods mentioned above. Their most common comorbidities were diabetes, hypertension, chronic kidney disease, and dyslipidemia.

Over the 721-day median follow-up, the mean (SD) length of time from diagnosis to Sac/Val initiation was 52.1 (14.3) days in the earlier initiation group (n = 67), 201.8 (127.3) days in the later-initiation group (n = 48), and 114.6 (110.9) days for the entire study population. An overall 18.3% experienced the primary composite outcome of HF hospitalization/cardiac-related death, but this rate was significantly lower in the earlier vs later group, at 10.4% vs 29.2%.

At the baseline study visit, mean diastolic blood pressure (DBP), mean arterial pressure (MAP), hemoglobin, and alanine aminotransferase (ALT) were higher in the earlier vs later-use group:

  • DBP: 73.3 (13.8) vs 68.2 (12.6) mm Hg
  • MAP: 89.3 (14.1) vs 84.8 (12.3) mm Hg
  • Hemoglobin: 14.2 (1.8) vs 13.0 (2.4)
  • ALT: 32.7 (30.3) vs 20.6 (14.9)

In addition, the earlier group had a greater increase in ejection fraction before 6 months compared with the later group, at 35.2% (11.9%) vs 27.8% (8.8%), as well as more prominent left atrial (LA) reverse remodeling, at 55.2 (17.1) vs 43.6 (14.3) mL/m2. However, the later-use group had a larger ejection fraction improvement after 6 months vs the earlier-use group: 37.2% (11.2%) vs 34.0% (8.8%).

LA volume change was shown to be continuous in the earlier-use group but stagnated in the later-use group after 18 months: 43.6 (14.3) vs 55.2 (17.1) ml/m2.

The secondary outcomes of HF hospitalization, readmission before and after Sac/Val initiation, and cardiac and all-cause death occurred at higher rates in the later vs early group:

  • HF hospitalization: 29.2% vs 10.4%
  • Readmission before Sac/Val: 20.8% vs 1.5%
  • Readmission after Sac/Val: 12.5% vs 9.0%
  • Cardiac death: 2.1% vs 1.5%
  • All-cause death: 4.2% vs 1.5%

Ischemic heart disease and delayed use of Sac/Val were shown to be independent predictors of HF hospitalization, with increased risks of 333% (HR, 4.333; 95% CI, 1.811-10.366) and 187% (HR, 2.871; 95% CI, 1.158-7.113), respectively.

The study authors emphasize that more studies need to investigate the impact of earlier initiation of Sac/Val and that among individuals with HFrEF, a comprehensive approach to managing their heart disease is best.

“Based on study findings, it is important to start Sac/Val as soon as possible, even in patients with HF who were discharged from the hospital without its use,” they concluded. “The earlier use of Sac/Val after the stabilization of HF symptoms needs to be emphasized to reduce adverse clinical events and to achieve earlier LV reverse remodeling as well as prolonged effect on LA reverse remodeling, implying diastolic function preservation.”


Oh J-H, Lee J-M, Lee H-J, et al. The benefits of earlier use of sacubitril/valsartan in de novo heart failure with reduced ejection fraction patients. ESC Heart Fail. Published online April 28, 2022. doi:10.1002/ehf2.13940

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