ARNIs (Sacubitril/Valsartan)

Introduction

Heart failure (HF) represents one of the most significant public health challenges of the modern era, affecting more than 64 million individuals globally. Despite major advances in device therapy, revascularization, and pharmacology, morbidity and mortality from heart failure remain unacceptably high. For decades, the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS) were the primary targets of pharmacotherapy, with ACE inhibitors, ARBs, and beta-blockers forming the foundation of treatment.

Yet, even with these interventions, patients continued to experience progressive ventricular dysfunction, recurrent hospitalizations, and early death. This gap prompted the search for novel therapies targeting additional pathways of heart failure pathophysiology.

A major breakthrough came with the development of angiotensin receptor–neprilysin inhibitors (ARNIs), represented clinically by sacubitril/valsartan (Entresto). By simultaneously inhibiting RAAS and enhancing the beneficial natriuretic peptide system, ARNIs provide a synergistic, dual-mechanism approach that has transformed the landscape of heart failure therapy.

This article explores the history, molecular basis, pharmacology, clinical evidence, guideline recommendations, safety considerations, and future perspectives of ARNIs, with emphasis on their revolutionary impact in heart failure treatment.

Historical Background: From ACE Inhibitors to ARNIs

The therapeutic journey in heart failure reflects the gradual understanding of its neurohormonal basis.

Pre-RAAS era: Early treatments like digitalis and diuretics focused mainly on symptom relief but failed to influence long-term outcomes.
ACE inhibitors (1980s): Pioneering trials (CONSENSUS, SOLVD) demonstrated survival benefits, establishing RAAS inhibition as a cornerstone.
ARBs (1990s): Provided alternatives to ACE inhibitors for patients intolerant to cough or angioedema.
Mineralocorticoid receptor antagonists (2000s): RALES and EMPHASIS-HF trials proved additional mortality reduction.
ARNI (2010s): A paradigm shift with PARADIGM-HF, showing sacubitril/valsartan’s superiority over enalapril in reducing mortality and hospitalization.

The evolution highlights the need for multi-pathway modulation in HF, with ARNIs representing the first drug class to harness both RAAS suppression and augmentation of endogenous vasodilatory peptides.

Pathophysiology of Heart Failure: Rationale for ARNI Therapy

Heart failure is not merely a pump failure but a neurohormonal disorder.

The Maladaptive RAAS and SNS

Chronic RAAS activation → vasoconstriction, sodium retention, fibrosis, hypertrophy.
Persistent SNS drive → tachycardia, arrhythmias, increased myocardial oxygen demand.

The Protective Natriuretic Peptide (NP) System

Includes atrial NP (ANP), B-type NP (BNP), and C-type NP.
Benefits: vasodilation, natriuresis, inhibition of fibrosis, suppression of RAAS/SNS.
Limitation: rapidly degraded by neprilysin, limiting their therapeutic utility.

Therapeutic Concept of ARNIs

Combine ARB (valsartan) → blocks AT1 receptors and prevents angiotensin II effects.
With neprilysin inhibitor (sacubitril) → enhances NP activity, counteracting remodeling and congestion.
Dual action = reduced maladaptive neurohormones + enhanced protective peptides.

Molecular Mechanism of Sacubitril/Valsartan

Sacubitril

Prodrug converted to active metabolite (LBQ657).
Inhibits neprilysin (neutral endopeptidase), which degrades ANP, BNP, bradykinin, and adrenomedullin.
Results: increased NP levels → vasodilation, natriuresis, diuresis, reduced hypertrophy.

Valsartan

Selective AT1 receptor antagonist.
Blocks angiotensin II–mediated vasoconstriction, aldosterone release, and fibrosis.

Combined Effect

Reduced afterload and preload.
Improved renal sodium handling.
Enhanced reverse remodeling.
Lower neurohormonal stress.

This synergy explains why ARNIs outperform ACEIs/ARBs alone.

Pharmacokinetics and Pharmacodynamics

Administration: Oral, twice daily.
Absorption: Rapid; peak levels in 1–2 hours.
Metabolism: Sacubitril → LBQ657 via esterases.
Excretion: Renal and biliary routes.
Half-life: Valsartan ~9 hours; LBQ657 ~12 hours.

Dose adjustments are required in renal or hepatic impairment, and in patients previously on ACEIs (requires 36-hour washout to prevent angioedema risk).

Clinical Trials: Evidence for ARNIs

1. PARADIGM-HF (2014)

Design: 8,442 patients with HFrEF (EF ≤40%).
Comparison: Sacubitril/valsartan vs. enalapril.
Results:
- 20% reduction in CV death.
- 21% reduction in HF hospitalization.
- 16% reduction in all-cause mortality.
Conclusion: ARNIs superior to ACE inhibitors in HFrEF.

2. PARAMOUNT (2012)

Population: HFpEF (EF ≥45%).
Findings: Greater reduction in NT-proBNP levels and improved left atrial size vs. valsartan.
Indicated possible benefits in HFpEF, though mortality benefits remain uncertain.

3. PARAGON-HF (2019)

Population: HFpEF (EF ≥45%).
Results: Did not meet primary endpoint, but trend toward benefit in women and EF 45–57%.
Suggests role in selected HFpEF subgroups.

4. TRANSITION and TITRATION studies

Evaluated initiation in acute HF and optimal up-titration strategies.
Demonstrated feasibility and safety of starting ARNIs early post-decompensation.

Overall, ARNIs established a new standard of care in HFrEF, with growing evidence in HFpEF.

Clinical Indications

Current FDA/EMA Approved Uses

Heart failure with reduced ejection fraction (HFrEF): NYHA II–IV, EF ≤40%, symptomatic despite optimal therapy.
Post-acute decompensated HF: Can be initiated in hospitalized patients after stabilization.

Off-Label / Investigational Uses

HFpEF: Evidence evolving (PARAGON-HF).
Post-MI remodeling: Ongoing trials suggest potential benefit.
Hypertension: ARNI lowers BP effectively, but not routinely indicated.

Practical Considerations in Clinical Use

Dosing

Start: 24/26 mg or 49/51 mg twice daily, depending on baseline therapy and patient profile.
Target: 97/103 mg twice daily.
Washout: 36 hours if switching from ACE inhibitor.

Monitoring

Blood pressure (risk of hypotension).
Renal function and potassium levels.
Symptoms of angioedema (rare but serious).

Safety Profile and Adverse Effects

Hypotension: Most common, due to vasodilatory effects.
Hyperkalemia: Especially in CKD or with MRAs.
Renal dysfunction: Monitor eGFR.
Angioedema: Rare, lower than with ACEIs but significant risk if not following washout rules.
Cough: Less frequent than with ACE inhibitors.

Overall, ARNIs are well tolerated, with discontinuation rates lower than enalapril in trials.

Comparative Advantages over ACEIs/ARBs

Feature	ACE Inhibitors	ARBs	ARNIs
RAAS blockade	Yes	Yes	Yes
NP enhancement	No	No	Yes
Effect on mortality (HFrEF)	Reduced	Reduced	Superior
Cough/Angioedema	Common (cough)	Rare	Less than ACEI
Hypotension	Moderate	Moderate	More frequent
Evidence in HFpEF	Limited	Limited	Emerging (subgroup benefit)

ARNIs thus represent a true therapeutic advancement, not just an incremental change.

Guideline Recommendations

ESC 2021: ARNIs recommended as first-line therapy (instead of ACEI) in symptomatic HFrEF patients.
ACC/AHA/HFSA 2022: Class I recommendation for ARNIs in HFrEF; ACEIs only if ARNI not feasible.
NICE (UK): Endorses ARNI use in chronic symptomatic HFrEF as replacement for ACEI/ARB.

This widespread endorsement reflects the magnitude of benefit observed in clinical practice.

Real-World Impact

Since their approval, ARNIs have demonstrated:

Reduction in hospitalization burden.
Improved patient quality of life scores.
Economic benefits through fewer admissions.
Uptake remains variable due to cost, physician familiarity, and access barriers.

Limitations and Challenges

Cost and accessibility: Higher than generic ACEIs/ARBs.
Limited HFpEF benefit: Not yet conclusive.
Need for monitoring: Especially BP and renal function.
Polypharmacy in HF: ARNIs must be integrated with beta-blockers, MRAs, and SGLT2 inhibitors.

Future Perspectives

HFpEF expansion: Ongoing trials to better define subgroups who benefit.
Combination therapies: Synergy with SGLT2 inhibitors, vericiguat, and novel anti-fibrotic agents.
Post-MI remodeling: Studies investigating initiation early after myocardial infarction.
Biomarker-guided therapy: Using NT-proBNP levels to titrate and optimize therapy.
Personalized medicine: Genetic profiling may identify patients most likely to respond to ARNIs.