Entresto Use in Heart Failure w Preserved Function

Aubrey J. Grant, MD

Heart failure is a pervasive diagnosis and unfortunately about 6.2 million adults in the United States suffer from this disease.1 Furthermore, heart failure represents a significant proportion of total healthcare expenditures including the cost of healthcare services, medicines to treat heart failure, and missed days of work. While we often focus on the management of heart failure with reduced ejection fraction, epidemiological studies report about 50% of all heart failure patients have preserved function.2 Heart failure patients with preserved function have similar rates of hospitalization and death when compared to heart failure patients with reduced function.2

While there are several treatment options that have proven mortality benefit in chronic heart failure patients with reduced function, the treatment options for patients with preserved function are limited. 

Following the results of the PARADIGM-HF trial, PARAGON-HF was an industry funded, multi-national, double blinded trial that attempted to determine whether entresto was more effective than valsartan at lowering the rate of total hospitalizations for heart failure and death from cardiovascular causes. The investigators of this trial randomly assigned 4822 patients with symptomatic heart failure with preserved function (left ventricular ejection fraction [LVEF] ≥ 45%) to entresto or valsartan alone. The primary endpoint was total hospitalizations for heart failure and death due to cardiovascular causes.

Entresto Use in Heart Failure w Preserved Function

Regarding the patient group studied; the mean age of the patients was 73 years, 52% were female, only 2% were black, and the average ejection fraction was approximately 57%.  The investigators found that entresto did reduce the rate of the primary endpoint by 13% (rate ratio, 0.87; P = .06). The data shows that the lower event rate was mostly driven by fewer hospitalizations for heart failure. Notably, death due to cardiovascular causes was essentially the same with 204 deaths in the Entresto group  and 212 deaths in the valsartan group.3

Following the PARAGON-HF trial, the FDA has now granted an expanded indication to Entresto that would allow for use of the therapy in at least some patients with heart failure and preserved ejection fraction (HFpEF). The manufacturer Novartis touts that this is the first time that there is a heart failure treatment with an indication that includes patients with preserved function. While it is truly an amazing feat to now have an FDA indicated drug for this patient population, the effect on hard cardiovascular outcomes as suggested by PARAGON-HF are marginal. Further studies should be conducted to determine whether the drug is more effective in certain patient populations in order to truly understand the potential benefits of entresto in heart failure with preserved function.

  1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association external icon Circulation. 2020;141(9):e139-596.
  2. 1.Gladden JD, Linke WA, Redfield MM. Heart failure with preserved ejection fraction. Pflugers Arch 2014;466:1037-1053
  3. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Düngen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1. PMID: 31475794.

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