Managing heart failure with sacubitril-valsartan: Why ARNIs stand out?

Heart failure (HF) is a major economic and health burden worldwide, characterized by the presence of dyspnea or limited exertion due to impaired cardiac ventricular filling and/or blood ejection. (1) The development of ARNIs has been one of the greatest breakthroughs of the present century that has ushered a new paradigm in the management of heart failure across the spectrum of ejection fractions (both reduced and preserved).

The following review aims to summarise the key aspects of ARNIs use in the management of heart failure in today's era, including the scientific evidence, guideline recommendations, and tips for physicians for initiating and switching to ARNIs in their heart failure patient populations.

Mechanism:

The key underlying mechanisms of HF include the autonomic nervous system, the renin-angiotensin-aldosterone system (RAAS), and the natriuretic peptide (NP) system. (2) Sacubitril/valsartan is the first of the class of dual neprilysin and angiotensin receptor inhibitors (ARNI). (3)

Moving forward from the era, where beta-blockers and ACE inhibitors/ARBs formed the key pillars of heart failure therapy, ARNIs have now been designated as the preferred agents due to the following trial-based evidence:

1. Reduced Mortality in HF Patients

The PARADIGM-HF study demonstrated a clear and early benefit of sacubitril/valsartan compared to enalapril, with a 20% relative risk reduction in the combined primary endpoint of CV death and HF hospitalization, as well as in the individual components of the primary endpoint.

These results contrast with those of many pivotal studies of ACEI/angiotensin II receptor antagonists (ARA II) (SOLVD-T, CHARM-Alternative, EMPHASIS-HF, ATLAS, HEAAL) where the reduction is more pronounced in HF hospitalizations than in CV death (4).

In addition, ARNI reduced the risk of death from any cause by 16% and improved the quality of life. (4)

2. Reduction of CV Mortality Due to Sudden Death

Further analysis of the PARADIGM study showed that approximately 80% of deaths in trial patients were due to CV causes with a 20% risk reduction observed in the ARNI vs. enalapril group. For sudden deaths (both resuscitated and non-resuscitated), a 22% risk reduction was observed in patients in the ARNI treatment arm compared to enalapril. (4)

3.  Effect on Ventricular Arrhythmias

The effect of ARNIs on ventricular arrhythmias was evaluated in a prospective, observational study in a cohort of 120 patients with HFrEF and an Implantable cardioverter-defibrillator (ICD) with remote monitoring capability. Patients in the study were treated with an ARNI for 9 months after having previously been on ramipril or valsartan for 9 months. The patients experienced clinical improvement, reduced NT-proBNP levels, improved left ventricular remodeling (increase in ejection fraction of ~5 points), and a significant reduction in arrhythmic load after switching to ARNI. (5)

4. Role in Acute decompensated HF

While the PARADIGM-HF trial has shown the superiority of sacubitril-valsartan in chronic HF, data in patients with acute decompensated HF (ADHF) was lacking. PIONEER-HF study randomized 881 patients with HFrEF who were hospitalized for ADHF and stabilized to receive sacubitril–valsartan or enalapril. (6)

Eight weeks after discharge it was observed that the sacubitril/valsartan group had a 29% greater reduction in NT-proBNP and a 42% lower rate of the composite clinical end point of CV death or HF rehospitalization than the enalapril group (6).

More importantly, the relative risk of the composite end point of CV death, HF rehospitalization, or LV assist device implantation during the 4-week extension phase was 33% lower in the continuous sacubitril/valsartan group than in the switchers. These points highlight the safety of initiating sacubitril-valsartan in stabilized ADHF patients. (6)

5. HFpEF

In contradistinction to successful evidence-based therapy for HFrEF, no therapies have been shown to definitively improve mortality or hospitalization in HFpEF. (7)

Trials of ACEIs, ARBs, β-blockers, and mineralocorticoid receptor antagonists (MRAs) have all failed to reduce mortality in patients with HFpEF. (7)

NT-pro BNP is a marker for the diagnosis and prognosis of HF. Reduction in NT-pro BNP levels in patients with LV ejection fraction ≥45% with sacubitril-valsartan was shown in the PARAMOUNT trial. It was found that NT-pro BNP levels significantly decreased in the ARNI group along with a 7% reduction of LA volume indicating reverse left atrial remodeling, a 9% improvement in the New York Heart Association class. (8)

Range of Use of Sacubitril/Valsartan in HFrEF Patients

In the last few years, several studies have been published on the range of use of sacubitril/valsartan in the various settings of HFrEF.(9,10) Besides the landmark PARADIGM trial discussed earlier, other studies giving supportive evidence for ARNI use are the TITRATION trial (11), on the possible modalities of titration of sacubitril/valsartan in clinical practice, the PIONEER (12)and TRANSITION (13) studies, which deal with the important topic of initiating sacubitril/valsartan in the acute HF setting, as well as the PRIME study(14), PROVE-HF(15) and EVALUATE-HF (16) studies, which provided insights into the reverse remodeling effect of sacubitril/valsartan.

Sacubitril/Valsartan Therapy in Clinical practice

Answering the common iffs and butts

A common issue that arises for the clinician is the uncertainty about whether ACEi/ARB therapy is sufficient in their apparently stable patients with HFrEF. The studies summarized above provide strong evidence for the superiority of sacubitril/valsartan, compared with conventional RAAS inhibition, in the outpatient setting. Importantly, the benefit of sacubitril/valsartan over enalapril was consistent, regardless of background therapy. (17)

Given that HF decompensation is the best clinical indicator of insufficiency of current HF treatment, available evidence prompts the substitution of an ACEi/ARB with sacubitril/valsartan also in this setting. (6) Initiation during hospitalization might allow for better titration and easier treatment of side effects.

Role in renal protection: It has been shown that sacubitril/valsartan seemed to partially mitigate the risk of hyperkalemia when the patient was already taking MRA, and long-term renal function seemed protected to a larger extent by sacubitril/valsartan compared with RAAS inhibitors. (18) These data on renal protection with sacubitril/valsartan were consistent across the spectrum of LVEF. (19)

Guideline recommendations:

In light of recent data from studies subsequent to PARADIGM-HF, it seems compelling and obvious that initiation of sacubitril/valsartan is preferred regardless of pretreatment with ACEi/ARB, as conceded by consensus documents published by the American College of Cardiology and European Society of Cardiology. (20,21)

Guide to physicians:

The standard recommendations and precautions of ARNI use are summarised in figures 1 and 2.

Fig 1

Fig. 2

Reference Fig. 1&2 - Mauro Gori, James L Januzzi, Emilia D'Elia, Ferdinando Luca Lorini, Michele Senni, Rationale for and Practical Use of Sacubitril/Valsartan in the Patient's Journey with Heart Failure and Reduced Ejection Fraction, Cardiac Failure Review 2021;7:e06.

Conclusion:

In patients with HFrEF, treatment with sacubitril/valsartan has been shown to be cost-effective (22) and superior to enalapril in reducing all-cause and cardiovascular mortality, including sudden cardiac death and HF death, as well as in reducing the rate of HF hospitalization and rehospitalization (23).

Initiation of ARNI is also associated with an early significant benefit, compared to treatment with enalapril, in both the chronic and the acute setting (12,13).

Sacubitril/valsartan administration has been shown to be safe and well-tolerated in a wide range of HFrEF patients and associated with a significant improvement in quality-of-life measures (24,25).

References:

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2. D'Elia E, Iacovoni A, Vaduganathan M, Lorini FL, Perlini S, Senni M. Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides. Eur J Heart Fail. (2017) 19:710–7.

3. Campbell DJ. Long-term neprilysin inhibition - implications for ARNIs. Nat Rev Cardiol. (2017) 14:171–86. doi: 10.1038/nrcardio.2016.200

4. Desai AS, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Chen F, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. (2015) 36:1990–7.

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6. Velazquez E, Morrow D, DeVore A et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N. Engl. J. Med. 380, 539–548 (2019).

7. Kuchulakanti PK. ARNI in cardiovascular disease: current evidence and future perspectives. Future Cardiol. 2020 Sep;16(5):505-515.

8. Solomon SD, McMurray JJV, Anand IS et al. Angiotensin– neprilysin inhibition in heart failure with preserved ejection fraction. N. Engl. J. Med. 381, 1609–1620 (2019).

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13. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019; 21:998–1007.

14. Kang DH, Park SJ, Shin SH, et al. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 2019;139:1354–65

15. Januzzi J, Prescott M, 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;322:1085–95

16. Desai A, Solomon S, Shah A, et al. Effect of sacubitril-valsartan versus enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2019;322:1077–84

17. Okumura N, Jhund PS, Gong J, et al. Effects of sacubitril/valsartan in the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) according to background therapy. Circ Heart Fail 2016;9:e003212.

18. Kristensen SL, Preiss D, Jhund PS, et al. Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial. Circ Heart Fail 2016;9:e002560.

19. Damman K, Gori M, Claggett B, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail 2018;6:489–98

20. Seferovic P, Ponikowski P, Anker S, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:1169–86

21. Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2019;74:1966–11

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23. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. (2014) 371:993–1004. doi: 10.1056/NEJMoa1409077

24. Chandra A, Lewis EF, Claggett BL, Desai AS, Packer M, Zile MR, et al. Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. (2018) 3:498–505. doi: 10.1001/jamacardio.2018.0398

25. Polanczyk CA, Claggett B, Packer M, Zile M, McMurray J, Rouleau JL, et al. Impact of cardiovascular and non-cardiovascular hospitalization on quality of life in patients with heart failure and reduced ejection fraction. J Am College Cardiol. (2020) 75:1095. doi: 10.1016/S0735-1097(20)31722-8