News & Perspective

Stealing the spotlight: Early angiotensin receptor-neprilysin inhibition (ARNI) for heart failure treatment

4 months ago, OP Editor

Despite continuous efforts to prevent heart failure (HF), cardiovascular diseases (CVDs) are currently the leading cause of death in developed countries, specifically among the aging population.1 At present, medical therapies such as inotropic agents, vasodilators and loop diuretics have only shown moderate success (52.6% of patients die within five years) at treating patients with HF.1 Nonetheless, results from PIONEER-HF trial, together with data from the PARADIGM-HF study, sheds new light on the benefits of early angiotensin receptor-neprilysin inhibition (ARNI) therapy towards the management of patients suffering from heart failure with reduced ejection fraction (HFrEF).2

Heart diseases are universal and affect people of all ages and remain at the forefront for the mortality rates worldwide.1 Although HF is manageable with significant breakthroughs in the treatment of chronic HF, the condition still carries a poor prognosis. As such, patients with HF experience an overall reduction in the quality of life. Subsequently, the onset of acute heart failure (AHF), a potentially life-threatening condition induced by the rapid emergence of new or worsening symptoms of HF, only exacerbated the problem, resulting in the hospitalization of patients. Moreover, therapy for AHF has not changed adequately in over four decades.

Presently, the standard guideline-directed medical treatment (GDMT) includes beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and aldosterone antagonists (AAs).3 Today, treatment is highly dependent on using decongestant therapy with intravenous diuretics and vasodilators critical for hemodynamic stability. In general, the guidelines recommend the use of these main classes of medications at maximally tolerated dosages. However, less than 25% of HF patients with HFrEF, are on the appropriate medical regimen with a majority of patients being on lower titrated doses due to the worsening of renal function associated with GDMT therapy. As a result, the mortality rates for HF, in particular AHF, remains high.3

Interestingly, the early administration of ARNI, consisting of valsartan and sacubitril, has demonstrated significant benefits to patients with HF and reduced ejection fraction. The successful mechanism of sacubitril/valsartan is attributed to both the inhibition of the renin-angiotensin-aldosterone system with valsartan and augmentation of the natriuretic peptides through neprilysin inhibition by sacubitril, which is corroborated by the results from both the PARADIGM-HF and PIONEER-HF studies.

PARADIGM-HF, a randomized clinical trial has demonstrated the superior effectiveness of sacubitril/valsartan over enalapril, an ACE inhibitor, in a sample of more than 8,000 patients with systolic HF.4 Remarkably, due to the compelling evidence of sacubitril/valsartan in improving the cardiovascular mortality rates for HF hospitalizations in ambulatory patients, the Food and Drug Administration (FDA) has approved the use of sacubitril/valsartan in modulating symptomatic HFrEF.4

Additionally, the PIONEER-HP clinical trial was also designed to understand precisely if the mechanism of sacubitril/valsartan or the more significant blockage of renin-angiotensin-aldosterone system accounts for the improved efficacy outcome. A 29% greater reduction was observed in the primary endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in the fourth and eighth weeks, by sacubitril/valsartan compared to enalapril patients (95% CI: 0.63-0.81; p<0.0001).2

Furthermore, the PIONEER trial, an open-label extension of 8 weeks after randomization, patients in both arms (sacubitril/valsartan n=417, lisinopril n=415) receiving sacubitril/valsartan for four weeks in an open-label study, highlighted a significant 46% reduction in the risk of a composite of death, heart failure re-hospitalization (hospital stay >24 hours), requirement for left ventricular assist device (LVAD) insertion or listing for cardiac transplantation compared to enalapril over eight weeks.2 The study enumerated the early administration of ARNI therapy in reducing the risk of CVDs or HF hospitalization in patients with HFrEF and chronic heart failure (NYHA Class II-IV). Notable examples are evident from the rates of serious adverse events (AEs) occurring with a frequency of ≥0.5%. Finally, safety and tolerability analyses illustrated similar levels of symptomatic hypotension in both arms (enalapril 12.7%, sacubitril/valsartan 15.0%; RR=1.18; 95% CI: 0.85-1.64), comparable hyperkalemia (enalapril 9.3% vs. sacubitril/valsartan 11.6% RR=1.25; 95% CI: 0.84-1.84), and similar kidney-related AEs (enalapril n=75, sacubitril/valsartan n=75, RR=1.00; CI: 0.75-1.34).2

In conclusion, the main findings from PIONEER-HF promoted the early induction of ARNI therapy in patients with ADHF for reducing re-hospitalization for HF. Notably, the primary endpoint results highlighted a substantial reduction in NT-proBNP and strongly supported the excellent benefits of the drug, together with the lack of excess risk of sacubitril/valsartan in patients suffering from ADHF.

  1. Velazquez E, et al. Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure:

    New England Journal of Medicine, 2018: 380(11):1090-1090.

  2. DeVore AD, et al. Initiation of angiotensin-neprilysin inhibition after acute decompensated

    heart failure: Secondary analysis of the open-label extension of the PIONEER-HF trial JAMACardiol 2019.

  3. Balakumaran, K et al., Evaluation of a guideline-directed medical therapy titration program in patients with heart failure with reduced ejection fraction. IJC Heart & Vasculature,2019(22):1-5.
  4. Correia, L. Paradigm-HF: a Paradigm Shift in Heart Failure Treatment. Arquivos Brasileiros de Cardiologia.2016(106): 77–79.


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