American Journal of Cardiovascular Drugs

, Volume 19, Issue 1, pp 21–36 | Cite as

Neprilysin Inhibitors: Filling a Gap in Heart Failure Management, Albeit Amidst Controversy and at a Significant Cost

  • Antonis S. ManolisEmail author
  • Theodora A. Manolis
  • Antonis A. Manolis
  • Helen Melita
Review Article


Dual angiotensin and neprilysin inhibition using the combination drug sacubitril–valsartan has ushered in a new era in the treatment of heart failure (HF). The randomized controlled PARADIGM-HF trial, which randomized 8399 patients with HF to enalapril or sacubitril–valsartan, showed a 20% reduction in mortality and HF hospitalization with the new drug. This has been heralded as a step toward filling a crucial gap in HF management by providing strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin–angiotensin system alone in stable patients with chronic HF as it negates the deleterious effects of angiotensin while concomitantly augmenting the beneficial effects of the endogenous natriuretic peptide system. This new therapy is costly, and other confirmatory studies have been lacking for over 2 years since its approval by major regulatory authorities. As such, controversy and heated discussions have amassed, as has detailed information from a plethora of secondary analyses of this pivotal trial about the pros and cons of this promising new therapeutic strategy in HF management. The aim of this review was to provide a critical assessment of all these aspects.


Compliance with ethical standards

Conflict of interest

ASM, TAM, AAM, and HM have no conflicts of interest that might be relevant to the contents of this manuscript.


No external funding was used in the preparation of this manuscript.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Antonis S. Manolis
    • 1
    Email author
  • Theodora A. Manolis
    • 2
  • Antonis A. Manolis
    • 3
  • Helen Melita
    • 4
  1. 1.Third Department of CardiologyAthens University School of MedicineAthensGreece
  2. 2.Zakynthos HospitalZakynthosGreece
  3. 3.Patras University School of MedicinePatrasGreece
  4. 4.Onassis Cardiac Surgery CenterAthensGreece

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