In the News: LIFE Trial Sheds Light on Entresto Use in Advanced Heart Failure - OnePoint Patient Care

In the News: LIFE Trial Sheds Light on Entresto Use in Advanced Heart Failure

ACE-inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are mainstays of heart failure treatment. But, if you have heart failure patients on your census, it might seem like more of them are taking sacubitril/valsartan (marketed as Entresto) – a sign that providers are keeping up with the 2021 update to the American College of Cardiology’s (ACC) heart failure guidelines.1 The latest recommendation is to use Entresto over ACEIs/ARBs in most cases, even as initial therapy, due to demonstrated reductions in death, hospitalizations, improved cardiac function and reversed cardiac remodeling.

Improved outcomes aside, Entresto’s prominent role in therapy is likely frustrating news for payers. It’s a brand name drug that costs substantially more than ACEIs/ARBs (the average wholesale price is around $700 for one month of treatment)2 – not an easy pill to swallow for hospices with capitated reimbursement rates.

Entresto’s approval for use in New York Heart Association (NYHA) class II to IV heart failure and its inclusion in the guidelines is largely based on findings from PARADIGM-HF.1,3 This trial demonstrated Entresto’s superiority over enalapril (an ACEI) for reducing the risk of death and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF).A notable limitation of PARADIGM-HF and other studies cited in the guideline update is that very few patients (≤1.8%) had NYHA class IV heart failure, the most severe form of the disease.4-6

To better understand how Entresto performs in advanced HFrEF, researchers conducted the LCZ696 in Advanced Heart Failure (LIFE) trial to assess its efficacy and safety compared to valsartan (an ARB).7 LIFE exclusively studied patients with class IV heart failure. Investigators were surprised to learn that Entresto wasn’t superior to valsartan for efficacy, tolerability, or safety — contrary to what guidelines and other trials imply. In fact, Entresto may do more harm than good in sicker patients; patients taking it had more hypotension and hyperkalemia. 3,7

On May 17, 2021, lead author Douglas L. Mann, MD presented results from the LIFE trial at the American College of Cardiology’s Annual Scientific Session (ACC.21).“This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF,” Mann said, “although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan.”In a follow-up interview Dr. Mann added, “In a group of people that’s extremely vulnerable, we don’t think that there’s any significant benefit of using a drug like sacubitril-valsartan as compared to something simple like valsartan.” 9

One of the study’s investigators, Dr. Sanjeev Gulati, also remarked, “Based on the LIFE study, I would not prescribe sacubitril/valsartan to patients with advanced heart failure. It reinforces the thought that the advanced heart failure patient is fundamentally and physiologically different than the less advanced heart failure patient.”10

It’s an interesting development, especially for hospice clinicians who care for patients with heart failure. Using ACEIs or ARBs instead of Entresto could be a “win-win” for patients AND hospice payers!

Written By:

John Corrigan, PharmD


Melissa Corak, PharmD

Clinical Pharmacists, OnePoint Patient Care


  1. Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure with Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021;77:772-810. doi 1016/j.jacc.2020.11.022
  2. AmerisourceBergen. Accessed June 24, 2021.
  3. Busko M. LIFE: ARNI Does Not Best Valsartan in Advanced Heart Failure. Medscape. June 8, 2021. Accessed June 16, 2021.
  4. McMurray J, Packer M, Desai A, et al. Angiotensin-Neprilysin Inhibition Versus Enalapril in Heart Failure. N Engl J Med. 2014;371:993-1004. doi: 1056/NEJMoa1409077
  5. Januzzi JL, Prescott MF, Butler J, et al. Association of Change in N-Terminal Pro–B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment with Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019;322(11):1085-1095. doi:1001/jama.2019.12821
  6. Desai AS, Solomon SD, Shah AM, et al. Effect of Sacubitril-Valsartan vs Enalapril on Aortic Stiffness in Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2019;322(11):1077-1084. doi:1001/jama.2019.12843
  7. Kumbhani D. LCZ696 in Advanced Heart Failure – LIFE. American College of Cardiology. May 17, 2021. Accessed June 24, 2021.
  8. Questions Raised About Common HF Drug Combination for More Severe Cases. U.S. Pharmacist. May 26, 2021. Accessed June 16, 2021.
  9. ACC 2021 Discussion: The LIFE Trial. Cardiac Failure Review. May 19, 2021. Accessed June 24, 2021.
  10. Phend C. Entresto Risky for Advanced Heart Failure? MedPage Today. May 17, 2021. Accessed June 17, 2021.