Angiotensin Receptor

Introduction

Heart failure (HF) continues to pose a major global health challenge, affecting an estimated 64 million people worldwide. Despite advances in drug therapy, patients with heart failure with reduced ejection fraction (HFrEF) still face high rates of morbidity and mortality.

For decades, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), and beta-blockers were the cornerstones of therapy. Later, mineralocorticoid receptor antagonists (MRAs) further improved outcomes. However, mortality and hospitalization rates remained unacceptably high.

The discovery and clinical introduction of angiotensin receptor–neprilysin inhibitors (ARNIs), particularly sacubitril/valsartan (Entresto®), marked a revolution in HF pharmacotherapy. This novel drug not only blocks the harmful effects of the renin–angiotensin–aldosterone system (RAAS) but also enhances beneficial natriuretic peptide signaling, offering dual-pathway modulation.

The PARADIGM-HF trial firmly established ARNIs as superior to ACE inhibitors in reducing mortality and hospitalizations. Consequently, modern guidelines now recommend ARNIs as a first-line therapy for HFrEF, when tolerated.

This article explores the mechanism of sacubitril/valsartan, evidence from PARADIGM-HF, and current guideline recommendations, while also addressing limitations, safety considerations, and clinical implications.

1. Sacubitril/Valsartan: Mechanism of Action

1.1 Dual Pathway Targeting

Sacubitril/valsartan is a first-in-class ARNI, combining:

Sacubitril: A neprilysin inhibitor.
Valsartan: An angiotensin II type-1 receptor (AT1R) blocker (ARB).

This dual action addresses both sides of HF pathophysiology:

Suppressing maladaptive RAAS activation.
Enhancing protective natriuretic peptide pathways.

1.2 Neprilysin Inhibition (Sacubitril Component)

Neprilysin is a neutral endopeptidase enzyme that degrades vasoactive peptides such as:
- Natriuretic peptides (ANP, BNP, CNP).
- Bradykinin.
- Adrenomedullin.
By inhibiting neprilysin, sacubitril increases the availability of these peptides, leading to:
- Natriuresis and diuresis → reduction in volume overload.
- Vasodilation → reduced afterload.
- Inhibition of fibrosis and hypertrophy → favorable cardiac remodeling.
- Reduced sympathetic activity and RAAS suppression.

1.3 RAAS Blockade (Valsartan Component)

Valsartan selectively blocks AT1 receptors, preventing angiotensin II–mediated:
- Vasoconstriction.
- Aldosterone release.
- Sodium and water retention.
- Sympathetic activation and myocardial hypertrophy.

1.4 Why Not Neprilysin Inhibition Alone?

Pure neprilysin inhibition (e.g., with omapatrilat) led to excessive accumulation of bradykinin, causing a high incidence of angioedema.
Combining neprilysin inhibition with ARB (not ACE inhibitor) provides balance:
- Preserves beneficial natriuretic peptide effects.
- Limits RAAS activation.
- Minimizes risk of angioedema compared to ACE-neprilysin inhibitor combos.

1.5 Clinical Effects of Sacubitril/Valsartan

Hemodynamic improvements: Decreased systemic vascular resistance, pulmonary capillary wedge pressure, and right atrial pressure.
Neurohormonal modulation: Lower levels of NT-proBNP, aldosterone, and troponin.
Structural benefits: Reverse left ventricular remodeling and reduced fibrosis.
Symptomatic benefits: Improved exercise tolerance, reduced hospitalizations, better quality of life.

2. Evidence from PARADIGM-HF Trial

2.1 Study Design

Published in 2014 (NEJM).
Largest HF trial to date, enrolling 8,442 patients with HFrEF (LVEF ≤40%).
Compared sacubitril/valsartan (200 mg BID) vs enalapril (10 mg BID), the gold standard at that time.
Median follow-up: 27 months.
Primary endpoint: Composite of CV death or HF hospitalization.

2.2 Key Results

Primary Outcome:
- 21.8% in sacubitril/valsartan group vs 26.5% in enalapril group.
- 20% relative risk reduction (RRR), absolute risk reduction (ARR) ~4.7%, NNT ≈ 21.
Cardiovascular Mortality:
- 13.3% vs 16.5% (HR 0.80).
All-Cause Mortality:
- 17.0% vs 19.8% (HR 0.84).
HF Hospitalizations:
- 12.8% vs 15.6% (HR 0.79).
Symptoms and Quality of Life:
- Significant improvements with sacubitril/valsartan.

2.3 Safety Findings

Lower incidence of renal impairment and hyperkalemia compared to enalapril.
Higher incidence of symptomatic hypotension.
Similar low incidence of angioedema, but slightly more with ARNI.

2.4 Subgroup Analyses

Benefits consistent across age, sex, ethnicity, baseline EF, diabetes status.
Particularly robust in patients with high baseline NT-proBNP.

2.5 Significance

PARADIGM-HF was the first trial to show superiority of a new agent over ACE inhibitors in HFrEF, shifting the treatment paradigm.
Demonstrated that augmenting natriuretic peptide pathways alongside RAAS blockade provides incremental benefit.

3. Current Guideline Recommendations

3.1 ESC Guidelines (2021)

Sacubitril/valsartan is recommended (Class I, Level A) in symptomatic patients with HFrEF (LVEF ≤40%), to replace ACE inhibitor or ARB, to reduce morbidity and mortality.
Should be considered as first-line therapy in place of ACE inhibitors.
Must not be given concomitantly with ACE inhibitors; requires a 36-hour washout after stopping ACEI to avoid angioedema.

3.2 ACC/AHA/HFSA Guidelines (2022)

ARNI preferred over ACEI or ARB in patients with HFrEF and NYHA II–III symptoms.
If ARNI not feasible, ACEI or ARB remain alternatives.
Class I recommendation for ARNI initiation in eligible patients.
ARNI also considered in hospitalized patients with acute decompensated HF, once stabilized.

3.3 Canadian and Asian Guidelines

Echo global recommendations:
- Prefer ARNIs in symptomatic HFrEF.
- Increasing adoption in Asia despite cost concerns.

4. Practical Considerations for Use

4.1 Initiation and Dosing

Start with 49/51 mg BID (sacubitril/valsartan).
Titrate to 97/103 mg BID (target dose).
Use lower starting dose (24/26 mg BID) in patients with:
- Hypotension.
- Renal impairment (eGFR 30–60 mL/min).
- Moderate hepatic impairment.

4.2 Monitoring

Blood pressure (risk of hypotension).
Renal function (creatinine, eGFR).
Serum potassium (hyperkalemia risk).
NT-proBNP (should fall with therapy; BNP rises due to neprilysin inhibition, so NT-proBNP is preferred marker).

4.3 Contraindications

Concomitant ACE inhibitor use (risk of angioedema).
History of angioedema with ACEI/ARB.
Pregnancy and breastfeeding.
Severe hepatic impairment.
Symptomatic hypotension (SBP <100 mmHg).

4.4 Adverse Effects

Hypotension (most common).
Hyperkalemia.
Renal dysfunction.
Angioedema (rare, slightly higher than ACEIs).

5. Beyond PARADIGM-HF: Ongoing Evidence

5.1 PARAGON-HF Trial

Tested sacubitril/valsartan in HF with preserved EF (HFpEF).
Did not meet primary endpoint, but showed benefit in reducing hospitalizations, especially in women and patients with EF 45–57%.
Suggests potential role in selected HFpEF subgroups.

5.2 TRANSITION and PIONEER-HF

Demonstrated safety and efficacy of initiating ARNI in hospitalized patients with acute decompensated HF.
Showed early reductions in NT-proBNP and favorable outcomes.

5.3 Real-World Data

Registries confirm that ARNIs reduce rehospitalization and mortality in diverse patient populations.

6. Limitations and Challenges

Cost: ARNIs are significantly more expensive than ACEIs/ARBs, limiting access in low- and middle-income countries.
Hypotension: Limits use in patients with low baseline blood pressure.
Uncertainty in HFpEF: More research needed to define benefit.
Long-term safety: While data are reassuring, concerns about neprilysin’s role in amyloid-β degradation and potential Alzheimer’s risk remain under investigation.