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Recent Heart Failure Studies Find Opportunity and Challenges with Sacubitril-Valsartan

Tuesday, September 29, 2020  
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Author: Kiley Margolis, PharmD Candidate 2021, Temple University School of Pharmacy

Faculty Advisor: Michael Barros, PharmD, BCPS, BCACP, BC-ADM, CDCES


Heart failure (HF) is a global health crisis affecting at least 26 million people worldwide and is increasing in prevalence. HF health expenditures are considerable and will increase dramatically with an ageing population. Despite the significant advances in therapies and prevention, mortality and morbidity are still high, and the quality of life of patients living with heart failure is poor.1 There are two distinct types of heart failure: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). HFpEF, also referred to as diastolic dysfunction, is characterized by reduced filling due to the inability of the ventricle to relax and a left ventricular ejection fraction (LVEF) of greater than or equal to 50%. Ejection fraction is the ratio of the total amount of a patient’s blood in the left ventricle compared to what is pumped through the body for use. A normal LVEF is between 55% - 70% with no sign of ventricular hardening. HFpEF is associated with high hospitalization rates, poor quality of life and increased mortality, and it is emerging as the predominant form of HF. There is currently no approved treatment for HFpEF.2  HFrEF, also known as systolic HF, is associated with chronic heart failure and is characterized by an enlargement of the left ventricular wall resulting in a LVEF of less than or equal to 40%.  There are approved treatment options for people living with HFrEF.2

In 2015, Entresto™ (sacubitril-valsartan), a novel combination angiotensin receptor-neprilysin inhibitor (ARNI), gained FDA approval to reduce the risk for cardiovascular death and hospitalization in patients with HFrEF and chronic heart failure as classified by the New York Heart Association (NYHA) classification system as class II-IV.2,3

In 2017, sacubitril-valsartan was included in the 2017 American College of Cardiology (ACC) Expert Consensus Decision Pathway regarding the treatment algorithm for guideline-directed medical therapy (GDMT) for heart failure patients.4 For the first time, these HF guidelines expanded to include an ARNI as part of a GDMT regimen for HFrEF to reduce morbidity and mortality. Initiation of an ARNI de novo without prior exposure to an ACEI or ARB was not recommended as there was no data to support this recommendation.4

In early 2019, the New England Journal of Medicine (NEJM) published the PIONEER-HF study which  compared sacubitril-valsartan versus enalapril and its effect on NT-proBNP, a biomarker which has been found to be predictive of HF.5 This trial provided evidence to support the safety of careful initiation of sacubitril-valsartan de novo for hospitalized patients with and without prior exposure to ACEI or ARB, selected for hemodynamic stability, with systolic blood pressure ≥100 mm Hg and without escalation of intravenous diuretics or vasodilators for 6 hours, and also without intravenous inotropic therapy within the previous 24 hours.5

PIONEER-HF was a biomarker-endpoint trial that randomized 881 adults with acute decompensated heart failure (ADHF) and reduced ejection fraction to sacubitril-valsartan or enalapril. Sacubitril-valsartan was associated with a greater reduction in NT-proBNP than enalapril (-47% vs. -25%; p-value <0.001)5. Both study drugs showed similar rates of adverse reactions. The PIONEER-HF study supports the initiation of ARNI therapy during ADHF as it is associated with a reduction in NT-proBNP and is generally well-tolerated.5

In late 2019, the NEJM published the PARAGON-HF study which compared sacubitril-valsartan to the active comparator, valsartan, in patients with HFpEF. This phase III randomized trial compared the long-term efficacy and safety of sacubitril-valsartan versus valsartan alone in 4,822 patients with HFpEF.6 Results showed a 13% reduction in the primary composite endpoint of total (first and recurrent) heart failure hospitalizations and cardiovascular death but missed statistical significance (p=0.059).6 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).7 NYHA class improved in 15% 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).7 The mean change at 8 months in the Kansas City Myopathy Questionnaire (KCCQ), a self-administered quality of life questionnaire for patients with HF, was 1 point out higher out of 100 points (95% CI, 0.0 to 2.1) in the sacubitril–valsartan group; demonstrating a slight improvement in quality of life. Patients in the sacubitril–valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia.7 While the study missed statistical significance of the primary endpoint, the evidence as a whole demonstrates a potential overall benefit with sacubitril-valsartan compared with valsartan in HFpEF, particularly in patients with an ejection fraction below normal.

In addition to studies evaluating an ARNI in HFpEF, several studies are underway to evaluate morbidity and mortality effects of sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy on patients with HFpEF. One such study is the EMPEROR-Preserved trial. This study is evaluating the use of empagliflozin as an add-on treatment to current HFpEF therapeutics and is assessing time-to-first event analysis of the combined risk for cardiovascular death or hospitalization for heart failure patients with HFpEF with or without type 2 diabetes.9 Another study, called the DELIVER trial, is evaluating the use of dapagliflozin, when added to standard of care, to reduce the composite of CV death and HF events in patients with HFpEF.10 

While the PIONEER-HF study demonstrated a positive outcome for additional therapies in the treatment of HFrEF, based on the aforementioned information, there is hope that researchers are close to a novel HFpEF treatment.




  1. Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Card Fail Rev. 2017;3(1):7–11.
  2. Initiation of Novartis Entresto in-hospital included in the new ACC Expert Consensus Decision Pathway developed to improve management of hospitalized heart failure patients. Published September 2019. Accessed January 5, 2020.
  3. Fala L. Entresto (Sacubitril/Valsartan): First-in-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved for Patients with Heart Failure. Am Health Drug Benefits. 2015;8(6):330–334.
  4. Yancy C, Januzzi J, Allen L, 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2018 Jan, 71 (2) 201-230.
  5. Velazquez E, Morrow D, DeVore A, Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7, 380:539-548.
  6. Novartis PARAGON-HF trial suggests Entresto® benefit in HFpEF patients but narrowly misses primary endpoint. Published September 2019. Accessed January 5, 2020.
  7. Solomon S, McMurray JV, Anand IS, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Sep 1; Published online 2019 Sep 1.
  8. Hollenberg S, Stevenson L, Ahmad T, 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure. J Am Coll Cardiol. 2019 Oct;74 (15):1966-2011.
  9. Anker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial. Eur J Heart Fail. 2019 Oct;21(10):1279-1287.
  10. Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure. (DELIVER). Accessed May 13, 2020.

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