The Role of Neprilisin Inhibitor in the Pathophysiology of Chronic HF:

a Change in the Paradigm

Anggia Chairuddin Lubis

Department of Cardiology and Vascular Medicine
Faculty of Medicine Universitas Sumatra Utara

Heart failure is a global pandemic affecting an estimated 26 million people

worldwide and resulting in more than 1 million hospitalizations annually in both
the United States and Europe. Patients with heart failure typically experience
several acute episodes interspersed with periods of stable, chronic disease.
Following an acute episode, it is therefore important to ensure that all patients
receive and continue to receive the medications known to be effective in chronic
heart failure. Although the outcomes for ambulatory HF patients with a reduced
ejection fraction (EF) have improved with the discovery of multiple evidence-
based drug and device therapies, hospitalized heart failure (HHF) patients
continue to experience unacceptably high post-discharge mortality and
readmission rates that have not changed in the last 2 decades.1

Halting or slowing the progression of the disease is important, as most

death due to heart failure occur during episodes of acute decompensation, for
which very few new evidence-based medicines have been developed in the past
20–30 years. In addition, the proportion of HHF patients classified as having a
preserved EF continues to grow and may overtake HF with a reduced EF in the
near future. However, the prognosis for HF with a preserved EF is similar and
there are currently no available disease- modifying therapies.1-2 Moreover, co-
morbidities are prevalent in patients with chronic HF and are related to the
severity of the disease.3

A new paradigm in heart failure management is needed to solve heart

failure problems.
 Figure 1. Success and failure of Heart Failure studies.4

Angiotensin-converting–enzyme (ACE) inhibitors have been the

cornerstone of the treatment for heart failure and a reduced ejection fraction for
nearly 25 years, since enalapril was shown to reduce the risk of death in two trials.
Long-term treatment with enalapril decreased the relative risk of death by 16%
among patients with mild-to-moderate symptoms. While angiotensin- receptor
blockers (ARBs) are recommended primarily for patients who have unacceptable
side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies
showed that the use of beta-blockers and mineralocorticoid-receptor antagonists,
when added to ACE inhibitors, resulted in incremental decreases in the risk of

death of 30 to 35% and 22 to 30%, respectively.5-13

Figure 2. Survival rates in chronic HF have improved with the introduction of
new therapies 6,11,12,14

Neprilysin, a neutral endopeptidase, degrades several endogenous

vasoactive peptides, including natriuretic peptides, bradykinin, and
adrenomedullin. Inhibition of neprilysin increases the levels of these substances,
countering the neurohormonal over activation that contributes to vasoconstriction,
sodium retention, and maladaptive remodeling. Combined inhibition of the renin–
angiotensin system and neprilysin had effects that were superior to those of either
approach alone in experimental studies, but in clinical trials, the combined
inhibition of ACE and neprilysin was associated with serious angioedema.15

PARADIGM_HF provides a new insights in heart failure management, by

combining Sacubitril and valsartan, a novel drug which delivers simultaneous
neprilysin inhibition and AT1 receptor blockade. This double-blind trial randomly
assigned 8442 patients with class II, III, or IV heart failure and an ejection
fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily)
or enalapril (at a dose of 10 mg twice daily), on top of recommended therapy. The
primary outcome was a composite of death from cardiovascular causes or
hospitalization for heart failure.
Figure 3. Sacubitril/valsartan simultaneously enhances beneficial effects of NPs
while blocking detrimental effects of the RAAS.16

The trial was stopped early, according to prespecified rules, after a median
follow-up of 27 months, because the boundary for an overwhelming benefit with
LCZ696 had been crossed. LCZ696 shows benefit in reducing cardiovascular
death (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001), risk of hospitalization
for heart failure by 21% (P<0.001), decreased the symptoms and physical
limitations of heart failure (P=0.001), lower proportions with renal impairment,
hyperkalemia, and cough than the enalapril group. However the LCZ696 group
had higher proportions of patients with hypotension and non serious
angioedema.15 LCZ696 has been adopted in the current European Society of
Cardiology and American College of Cardiology Heart Failure Guidelines since
2016, with class I recommendation in selected patients.

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