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Abstract

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome characterized by the heart’s inability to pump sufficient blood, leading to symptoms such as dyspnea, fatigue, and fluid retention. Traditional treatment approaches have included angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). However, despite optimal medical therapy, many patients continue to experience significant morbidity and mortality. The advent of Angiotensin Receptor-Neprilysin Inhibitors (ARNis) represents a significant advancement in the treatment of HFrEF. ARNis, such as the combination of sacubitril and valsartan, provide a dual mechanism of action by simultaneously inhibiting the renin-angiotensin-aldosterone system (RAAS) through angiotensin II receptor blockade and enhancing natriuretic peptide activity by inhibiting neprilysin, an enzyme responsible for the degradation of natriuretic peptides. This combination has shown to provide superior clinical outcomes compared to traditional therapies. The pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the risk of cardiovascular death and heart failure hospitalization compared to enalapril, an ACEI, in patients with HFrEF. The benefits of ARNis extend beyond the improvement of hemodynamics; they also include beneficial effects on myocardial remodeling, reduction in hospitalizations, and improved quality of life. However, ARNis are not without challenges. The most common adverse effects include hypotension, hyperkalemia, and renal dysfunction, which require careful patient selection and monitoring. Additionally, the cost of ARNis may pose a barrier to widespread use, although their long-term benefits may offset initial expenditures.

Keywords

HFrEF, ARNis, RAAS, ACIEs, ARBs, MRAs, Remodeling

Introduction

Heart failure with reduced ejection fraction (HFrEF) is a condition characterized by the heart’s inability to pump blood effectively, leading to symptoms such as shortness of breath, fatigue, and fluid retention. Traditionally, the management of HFrEF has relied on a combination of lifestyle modifications, diuretics, beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor blockers (ARBs). While these therapies have significantly improved the prognosis of patients with HFrEF, ongoing research has sought to further enhance treatment outcomes by targeting additional pathways involved in the pathophysiology of heart failure. One of the most significant advancements in the treatment of HFrEF in recent years is the development of angiotensin receptor blocker-neprilysin inhibitors (ARNIs). ARNIs represent a novel therapeutic approach that combines the benefits of ARBs with the unique effects of neprilysin inhibition. HFrEF is associated with neurohormonal activation, including the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. This neurohormonal activation contributes to vasoconstriction, sodium and water retention, and increased cardiac workload, which exacerbates heart failure symptoms and progression. Traditional therapies such as ACE inhibitors and ARBs primarily target the RAAS, reducing the harmful effects of angiotensin II and aldosterone. However, another important pathway in heart failure involves the natriuretic peptide system, which promotes vasodilation, natriuresis (excretion of sodium), and diuresis. Natriuretic peptides are beneficial in heart failure because they counteract the effects of neurohormonal activation, leading to reduced blood pressure, decreased cardiac workload, and improved fluid balance. Unfortunately, these peptides are broken down by the enzyme neprilysin, limiting their beneficial effects. ARNIs, by inhibiting neprilysin, prevent the breakdown of natriuretic peptides, thus enhancing their positive effects. When combined with an ARB like valsartan, which blocks the detrimental effects of angiotensin II, ARNIs offer a dual mechanism that targets both

BACKGROUND AND RATIONALE:

Heart failure with reduced ejection fraction (HFrEF) is a condition where the heart’s ability to pump blood effectively is compromised, leading to symptoms like fatigue, dyspnea (shortness of breath), and fluid retention. The condition is associated with poor clinical outcomes, including high mortality and frequent hospitalizations. Traditional treatments for HFrEF have focused on blocking the renin-angiotensin-aldosterone system (RAAS) using ACE inhibitors or ARBs, which help reduce the harmful effects of neurohormonal activation in heart failure. However, despite these therapies, the prognosis for many patients remains poor, necessitating the development of new therapeutic strategies. Angiotensin receptor blocker-neprilysin inhibitors (ARNIs) represent a novel class of medications designed to target multiple pathways involved in the pathophysiology of HFrEF. The combination of an ARB with a neprilysin inhibitor offers a dual approach: reducing the harmful effects of angiotensin II (via ARB) while enhancing the beneficial effects of natriuretic peptides (via neprilysin inhibition).

MECHANISM OF ACTION:

1. Neprilysin inhibition:

Neprilysin is an enzyme that degrades several vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Natriuretic peptides play a crucial role in cardiovascular homeostasis by promoting vasodilation, natriuresis (excretion of sodium), and diuresis (excretion of water), as well as inhibiting the RAAS and sympathetic nervous system. By inhibiting neprilysin, sacubitril (the neprilysin inhibitor in the ARNI sacubitril/valsartan) prevents the breakdown of these beneficial peptides, leading to prolonged vasodilation, reduced blood pressure, and decreased fluid overload.

2. Angiotensin ii receptor blockade:

Valsartan, the ARB component of the combination, selectively blocks the angiotensin II type 1 (AT1) receptor. Angiotensin II is a potent vasoconstrictor that also promotes sodium retention, aldosterone secretion, and sympathetic activation. By blocking the AT1 receptor, valsartan mitigates these harmful effects, thereby reducing vascular resistance, lowering blood pressure, and decreasing the heart’s workload.Together, these mechanisms provide a synergistic effect, addressing both the compensatory (but ultimately maladaptive) neurohormonal activation and enhancing the body’s natural defense mechanisms against heart failure progression.

Clinical evidence and efficacy:

1. Paradigm-hf trial:

The landmark PARADIGM-HF trial was a large, randomized, double-blind study that compared sacubitril/valsartan to enalapril, an ACE inhibitor, in over 8,000 patients with HFrEF. The trial was designed to evaluate whether the ARNI could reduce the risk of cardiovascular death or heart failure hospitalization compared to standard ACE inhibitor therapy.

Key results:

  • Primary Outcome: Sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization by 20% compared to enalapril.
  • Cardiovascular Mortality: There was a 20% reduction in the risk of cardiovascular death with sacubitril/valsartan.
  • Heart Failure Hospitalization: The risk of first hospitalization for heart failure was reduced by 21% in the sacubitril/valsartan group.
  • All-Cause Mortality: The study also found a 16% reduction in all-cause mortality with sacubitril/valsartan compared to enalapril.
  • Quality of Life: Patients treated with sacubitril/valsartan reported better quality of life scores, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), compared to those on enalapril.

2. Additional studies and real-world data:

Following the PARADIGM-HF trial, additional studies and real-world data have further supported the benefits of ARNIs in HFrEF. For example:

  • Transition Studies: Research has shown that transitioning patients from ACE inhibitors or ARBs to sacubitril/valsartan can be done safely with continued benefits.
  • Long-Term Outcomes: Extended follow-up studies have confirmed sustained reductions in mortality and hospitalization rates with ARNI therapy.
  • Subgroup Analyses: Further analyses have demonstrated that the benefits of sacubitril/valsartan are consistent across various subgroups, including those based on age, gender, baseline ejection fraction, and the presence of comorbidities like diabetes.

Safety and tolerability:

1. Common adverse effects:

The most common adverse effects associated with sacubitril/valsartan include:

  • Hypotension: Due to its potent vasodilatory effects, sacubitril/valsartan can cause significant drops in blood pressure, particularly in patients who are already on other antihypertensive agents.
  • Hyperkalemia: As with other RAAS inhibitors, sacubitril/valsartan can increase potassium levels, necessitating regular monitoring.
  • Renal Impairment: Some patients may experience worsening renal function, especially those with pre-existing kidney disease or those on high doses of the medication.
  • Cough and Angioedema: The risk of angioedema is a concern, particularly in patients with a history of ACE inhibitor-induced angioedema. However, the risk is lower than with ACE inhibitors.

2. Contraindications and precautions:

Concurrent Use with ACE Inhibitors: Sacubitril/valsartan should not be used in conjunction with ACE inhibitors due to the increased risk of angioedema. A washout period of at least 36 hours is required when switching from an ACE inhibitor to sacubitril/valsartan.

  • Pregnancy: Like other RAAS inhibitors, sacubitril/valsartan is contraindicated during pregnancy due to the risk of fetal harm.
  • History of Angioedema: Patients with a history of angioedema, especially related to prior RAAS inhibitor use, should avoid sacubitril/valsartan.

Guideline recommendations:

Based on the robust evidence from clinical trials, major cardiology guidelines, including those from the American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC), recommend sacubitril/valsartan as a first-line therapy for patients with HFrEF who can tolerate an ACE inhibitor or ARB. The guidelines emphasize the role of ARNIs in reducing mortality and morbidity in this population.

1. Treatment algorithms:

  • Initial Therapy: For patients with HFrEF and NYHA class II-IV symptoms, sacubitril/valsartan is recommended as an alternative to ACE inhibitors or ARBs.
  • Optimization: The goal is to titrate sacubitril/valsartan to the target dose of 97/103 mg twice daily, depending on tolerance, blood pressure, and renal function.
  • Monitoring: Regular monitoring of blood pressure, renal function, and potassium levels is essential to ensure the safe use of sacubitril/valsartan.

Cost-effectiveness and access:

1. Economic considerations:

While sacubitril/valsartan is more expensive than traditional therapies like ACE inhibitors or ARBs, its ability to significantly reduce hospitalizations and improve survival makes it cost-effective in the long term. Several health economic analyses have demonstrated that the higher upfront cost of sacubitril/valsartan is offset by reductions in healthcare costs associated with heart failure exacerbations and hospitalizations.

2. Access and insurance coverage:

In many countries, sacubitril/valsartan is covered by health insurance plans, although coverage policies may vary. Efforts are ongoing to ensure broader access to this medication, given its significant clinical benefits.

CONCLUSION

Angiotensin receptor blocker-neprilysin inhibitors, particularly sacubitril/valsartan, have transformed the management of heart failure with reduced ejection fraction. By combining the effects of neprilysin inhibition with angiotensin II receptor blockade, ARNIs offer a powerful and comprehensive approach to reducing mortality, hospitalization, and improving the quality of life in patients with HFrEF. The compelling evidence from clinical trials, combined with strong guideline recommendations, underscores the importance of ARNIs as a cornerstone in modern heart failure therapy. As research and clinical experience with ARNIs continue to grow, their role in heart failure management is expected to expand, offering hope to millions of patients worldwide.

REFERENCES

  1. K. Damman, M. Gori, B. Claggett, P.S. Jhund, M. Senni, M.P. Lefkowitz, M. F. Prescott, V.C. Shi, J.L. Rouleau, K. Swedberg, M.R. Zile, M. Packer, A.S. Desai, S.D. Solomon, J.J.V. McMurray, Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure, JACC Heart Fail 6 (6) (2018)
  1. 2.Y. Feng, Y. Yin, R. Deng, H. Li, Renal safety and efficacy of angiotensin receptorneprilysin inhibitor: a meta-analysis of randomized controlled trials, J. Clin. Pharm. Ther. 45 (6) (2020) 1235–1243.
  2. 3.A.V. Hernandez, V. Pasupuleti, N. Scarpelli, J. Malespini, M. Banach, A. M. Bielecka- Dabrowa, Efficacy and safety of sacubitril/valsartan in heart failure Compared to renin-angiotensin-aldosterone system inhibitors: a systematic review.And meta-analysis of randomised controlled trials, Arch. Med Sci. 19 (3) (2023)
  3. 4.R. Pontremoli, C. Borghi, P. Perrone Filardi, Renal protection in chronic heart Failure: focus on sacubitril/valsartan, Eur. Heart J. Cardiovasc Pharm. 7 (5) (2021) 445–452.
  4. 5L. Ni, C. Yuan, G. Chen, C. Zhang, X. Wu, SGLT2i: beyond the glucose-lowering Effect, Cardiovasc Diabetol. 19 (1) (2020) 98.
  5. 6.Y. Huang, C. Fang, Y. Zhang, L. Ma, H. Zhou, H. Ye, Effectiveness and safety of Angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 Inhibitors for patients with heart failure with reduced ejection fraction: a metaanalysis, J. Cardiovasc Med 24 (2) (2023) 123–131.
  6. S.D. Solomon, P.S. Jhund, B.L. Claggett, P. Dewan, L. Køber, M.N. Kosiborod, F. A.Martinez, P. Ponikowski, M.S. Sabatine, S.E. Inzucchi, A.S. Desai, O. Bengtsson, D. Lindholm, M. Sjostrand, A.M. Langkilde, J.J.V. McMurray, Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial, JACC Heart Fail 8 (10) (2020) 811–818.
  7. Y. Yan, B. Liu, J. Du, J. Wang, X. Jing, Y. Liu, S. Deng, J. Du, Q. She, SGLT2i Versus ARNI in heart failure with reduced ejection fraction: a systematic review And meta-analysis, ESC Heart Fail 8 (3) (2021) 2210–2219.
  8. 9.W.C. Lee, W.T. Chang, C.S. Hong, C.T. Liao, P.S. Huang, S.C. Huang, C.H. Lin, C. Y. Chiang, Z.C. Chen, J.Y. Shih, Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy, Front Biosci. (Landmark Ed. 28 (4) (2023) 81.
  9. J. Tang, L. Ye, Q. Yan, X. Zhang, L. Wang, Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism, Front Pharm. 13 (2022) 800490.
  10. M.J. Kim, H.N. Jang, H.N. Song, J.S. Lee, M.G. Kang, Acute Tubular Necrosis Associated with Angiotensin Receptor-neprilysin Inhibitor, Intern Med 61 (10) (2022) 1573–1576.
  11. W. Rattanavipanon, T. Sotananusak, F. Yamaae, A. Chandrsawang, P. Kaewkan, S.Nathisuwan, T. Yingchoncharoen, Real-world experience of angiotensin Receptor/neprilysin inhibitor (ARNI) usage in Thailand: a single-center, Retrospective analysis, BMC Cardiovasc Disord. 21 (1) (2021) 324.
  12. 1X. Wang, J. Pu, G. Wang, H. Xu, L. Liu, Z. Li, R. Qin, X. Zhao, M. Li, Z. Hao, H. Hu, Efficacy and safety analysis of angiotensin receptor neprilysin inhibition(ARNI)in Patients with heart failure: a real-world retrospective study, BMC Cardiovasc Disord. 23 (1) (2023) 343.
  13. 14P.K. Kuchulakanti, ARNI in cardiovascular disease: current evidence and future Perspectives, Future Cardiol. 16 (5) (2020) 505–515.

Reference

  1. K. Damman, M. Gori, B. Claggett, P.S. Jhund, M. Senni, M.P. Lefkowitz, M. F. Prescott, V.C. Shi, J.L. Rouleau, K. Swedberg, M.R. Zile, M. Packer, A.S. Desai, S.D. Solomon, J.J.V. McMurray, Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure, JACC Heart Fail 6 (6) (2018)
  1. 2.Y. Feng, Y. Yin, R. Deng, H. Li, Renal safety and efficacy of angiotensin receptorneprilysin inhibitor: a meta-analysis of randomized controlled trials, J. Clin. Pharm. Ther. 45 (6) (2020) 1235–1243.
  2. 3.A.V. Hernandez, V. Pasupuleti, N. Scarpelli, J. Malespini, M. Banach, A. M. Bielecka- Dabrowa, Efficacy and safety of sacubitril/valsartan in heart failure Compared to renin-angiotensin-aldosterone system inhibitors: a systematic review.And meta-analysis of randomised controlled trials, Arch. Med Sci. 19 (3) (2023)
  3. 4.R. Pontremoli, C. Borghi, P. Perrone Filardi, Renal protection in chronic heart Failure: focus on sacubitril/valsartan, Eur. Heart J. Cardiovasc Pharm. 7 (5) (2021) 445–452.
  4. 5L. Ni, C. Yuan, G. Chen, C. Zhang, X. Wu, SGLT2i: beyond the glucose-lowering Effect, Cardiovasc Diabetol. 19 (1) (2020) 98.
  5. 6.Y. Huang, C. Fang, Y. Zhang, L. Ma, H. Zhou, H. Ye, Effectiveness and safety of Angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 Inhibitors for patients with heart failure with reduced ejection fraction: a metaanalysis, J. Cardiovasc Med 24 (2) (2023) 123–131.
  6. S.D. Solomon, P.S. Jhund, B.L. Claggett, P. Dewan, L. Køber, M.N. Kosiborod, F. A.Martinez, P. Ponikowski, M.S. Sabatine, S.E. Inzucchi, A.S. Desai, O. Bengtsson, D. Lindholm, M. Sjostrand, A.M. Langkilde, J.J.V. McMurray, Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial, JACC Heart Fail 8 (10) (2020) 811–818.
  7. Y. Yan, B. Liu, J. Du, J. Wang, X. Jing, Y. Liu, S. Deng, J. Du, Q. She, SGLT2i Versus ARNI in heart failure with reduced ejection fraction: a systematic review And meta-analysis, ESC Heart Fail 8 (3) (2021) 2210–2219.
  8. 9.W.C. Lee, W.T. Chang, C.S. Hong, C.T. Liao, P.S. Huang, S.C. Huang, C.H. Lin, C. Y. Chiang, Z.C. Chen, J.Y. Shih, Sodium-Glucose Cotransporter 2 Inhibitors First Strategy Improve Decongestion in Patients with Symptomatic Heart Failure and Reduced Ejection Fraction When Compared to Angiotensin Receptor Neprilysin Inhibitor First Strategy, Front Biosci. (Landmark Ed. 28 (4) (2023) 81.
  9. J. Tang, L. Ye, Q. Yan, X. Zhang, L. Wang, Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism, Front Pharm. 13 (2022) 800490.
  10. M.J. Kim, H.N. Jang, H.N. Song, J.S. Lee, M.G. Kang, Acute Tubular Necrosis Associated with Angiotensin Receptor-neprilysin Inhibitor, Intern Med 61 (10) (2022) 1573–1576.
  11. W. Rattanavipanon, T. Sotananusak, F. Yamaae, A. Chandrsawang, P. Kaewkan, S.Nathisuwan, T. Yingchoncharoen, Real-world experience of angiotensin Receptor/neprilysin inhibitor (ARNI) usage in Thailand: a single-center, Retrospective analysis, BMC Cardiovasc Disord. 21 (1) (2021) 324.
  12. 1X. Wang, J. Pu, G. Wang, H. Xu, L. Liu, Z. Li, R. Qin, X. Zhao, M. Li, Z. Hao, H. Hu, Efficacy and safety analysis of angiotensin receptor neprilysin inhibition(ARNI)in Patients with heart failure: a real-world retrospective study, BMC Cardiovasc Disord. 23 (1) (2023) 343.
  13. 14P.K. Kuchulakanti, ARNI in cardiovascular disease: current evidence and future Perspectives, Future Cardiol. 16 (5) (2020) 505–515.

Photo
TUPE CHAITANYA KHANDERAO
Corresponding author

Department Of Pharmacology, Navsahyadri Institute Of Pharmacy, Pune.

Photo
Kisshor Vasant Otarri
Co-author

Department Of Pharmacology, Navsahyadri Institute Of Pharmacy, Pune.

Photo
Ajay Kale
Co-author

Department Of Pharmacology, Navsahyadri Institute Of Pharmacy, Pune.

Tupe Chaitanya Khanderao , Ajay Kale , Kisshor Vasant Otarri, A Review On The Role of Angiotensin Receptor-Neprilysin Inhibitors in Heart Failure with Reduced Ejection Fraction, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 9, 506-510. https://doi.org/10.5281/zenodo.13732514

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