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ENTRESTO: Honestly, It’s Not (Quite) For Everyone

Written by Joseph Kummer, MD, FACC

Only a generation ago the treatment for heart failure (HF) consisted of little more than diuretics to relieve symptoms. Digoxin was widely used but likely contributed little to no meaningful benefit. Medications that improve outcomes such as reduction in hospitalizations and prolongation of life were non-existent until the late 1980s. It was then that ACE Inhibitors (ACE-I) were proven to reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF).

Subsequently, angiotensin receptor blockers (ARBs) followed suit and were shown to have comparable benefits. But even 20 years after we landed on the moon, β-blockers were still thought to be contraindicated for patients with impaired systolic function. It wasn’t until the 1990s that β-blockers were found to actually greatly help, rather than hurt, a weakened heart. β-blockers and ACE/ARBs paved the way for the present guideline-directed medical therapy that revolutionized treatment and outcomes for patients suffering from heart failure.

Treatment Options Change Over Time

For about 20 years following widespread utilization of β-Blockers, there were several medications that showed promise but none that ultimately were as beneficial as β-Blockers and ACE/ARBs. Several of these are still appropriate in certain situations.

Examples include:

  • Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
  • Digoxin
  • Ivabradine
  • Hydralazine/nitrate combination therapy

Other treatments initially looked encouraging but ultimately were not shown to have more benefit than risk. These are now seldom used and include medications such as nesiritide and aliskerin. We also discovered that not all β-Blockers are created equal, with carvedilol and long-acting metoprolol emerging as the mainstay for β-Blocker therapy.

In the past seven years, there have been two categories of medications that I would consider to be “game-changers” for heart failure management.

  1. SGLT2 Inhibitors (as well as GLP-1 receptor agonists)
    There has been a tremendous amount of exciting data in the past few years regarding SGLT2 Inhibitors. Due to this, Bryan Heart has formed a cardiometabolic clinic to assist in treating patients with heart failure and diabetes/insulin resistance. We now know that even non-diabetics with HF benefit from these medications.

  2. Sacubitril-valsartan (Entresto)
    Sacubitril-valsartan likewise has been shown to have tremendous morbidity and mortality benefit for many HFrEF patients. It seems that every recent SGLT2 Inhibitor trial has only broadened the scope of patients who benefit from this therapy (now also including patients with impaired renal function). This stands in contrast to Entresto, however, where recent trials have shown that it is an excellent medication for some, but not all, heart failure patients.

Entresto’s Role in Heart Failure Patient Treatment

The primary trial establishing the role of sacubitril-valsartan was PARADIGM-HF in 2014.1 This trial evaluated patients with HFrEF (EF ≤ 40%) and NYHA Class II, III, or IV symptoms (most were Class II or III). It showed Entresto was superior to enalapril in reducing all-cause mortality, cardiac mortality and heart failure hospitalizations. It also showed an improved quality of life with Entresto.

Subsequently, we have expanded our analysis to include patients with heart failure with mid-range ejection fraction of 41-49% (HFmEF)2 as well as those with preserved ejection fraction (HFpEF).3 Both of these investigations ultimately failed to show a statistically significant reduction in heart failure hospitalizations or death with Entresto vs. an ACE or ARB. It has been frequently pointed out that there was a trend in both trials toward benefit and statistical significance was just barely missed.

Further analysis of PARAGON-HF trial looking at those with HFpEF ultimately did allow the drug to be approved for patients with chronic heart failure with preserved EF. The approval came with the caveat that the greatest benefit was in those with EF “below normal.” Given the negative composite findings of PARAGON-HF, it is somewhat surprising that Entresto was able to obtain this FDA approval in February of this year. A study did show fewer hospitalizations in HFpEF patients treated with Entresto for uncontrolled hypertension. This and other factors may have facilitated the FDA approval for HFpEF patients, but I personally would not feel compelled to use this in most HFpEF patients as of yet.

PARADIGM-HF only enrolled stable patients with chronic heart failure. Patients with acute heart failure were excluded. Dr. John Steuter, cardiologist at Bryan Heart, reviewed the PIONEER-HF on his blog a couple of years ago. This trial showed that it is also safe and effective to start Entresto on patients during an admission for acute decompensated heart failure.

In an effort to expand on the positive in-hospital results from PIONEER-HF, an industry-sponsored trial named PARADISE-MI was just pursued. The results were announced at the American College of Cardiology conference last month. This study compared Entresto to ramipril immediately following an acute MI in patients with no prior history of heart failure but an EF ≤ 40% at the time of their infarct. This study failed to show a reduction in:

  • Primary outcome of cardiovascular death,
  • First hospitalization for heart failure, or
  • Outpatient visit for heart failure during the 23 months of follow-up

Once again, there was extensive discussion among experts in the cardiology community about benefit trends with Entresto in subgroup analysis, etc. Ultimately, however, this was a well-designed study of over 5,000 patients that did not indicate a role for Entresto in the setting of acute myocardial ischemia, even with impaired LV systolic function.

Moving Forward

As recently as the 1980s, we had almost no medications to offer HF patients. Now, we have so many to choose from that we may need to caution against poly-pharmacy. Therefore, each medication should be carefully evaluated and used judiciously. I think that Entresto is an exceptional medication with very strong data to support its use in patients with Class II or III HF and an EF ≤ 40%. Although the FDA approved Entresto for HFmEF and HFpEF, in my opinion the data to support its use in this population is thus far not very compelling and likely not worth the expense and potential side effects of the medication. Recent data in patients with an acute coronary syndrome did not support a role for it in this setting.

With so many medications and so much data to review, contemporary treatment for HF can get quite complex.

As always, please feel free to contact us at Bryan Heart with questions regarding these or other treatments for your heart failure patients. Call 402-483-3333.


  1. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. McMurray JJV, Packer M, et al. N Engl J of Med. 2014;371(11).
  2. Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure. Solomon SD, Vaduganathan M, et al. Circulation. 2020;141(5):352
  3. Angiotensin-Neprilysin Inhibition in Patients with Heart Failure with Preserved Ejection Fraction. Solomon SD, McMurray JJV et al. N Engl J of Med. 2019;381(17).
kummer joseph

About Joseph Kummer, MD

Joseph Kummer, MD, is a cardiologist at Bryan Heart. Kummer is a graduate of The University of Nebraska Medical Center College of Medicine. He completed his residency at Northwestern Memorial Hospital and fellowship at Henry Ford Hospital. Kummer is certified by the American Board of Internal Medicine in Cardiovascular Disease and fellow of the American College of Cardiology

View Dr. Kummer’s physician profile


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