ARNI in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan (ARNI) should replace ACE inhibitors or ARBs in symptomatic HFrEF patients (EF ≤40%) already on guideline-directed medical therapy, as it significantly reduces cardiovascular death and heart failure hospitalizations by 20% compared to enalapril. 1, 2

Patient Selection and Eligibility

Before initiating ARNI, verify the following criteria 3, 4:

Ejection fraction ≤40% (benefits most clearly evident below normal LVEF)
Symptomatic heart failure (NYHA class II-IV) despite treatment with appropriate doses of beta-blocker, ACE inhibitor or ARB, and where appropriate, mineralocorticoid receptor antagonist
Serum potassium <5.2 mmol/L
eGFR ≥30 mL/min/1.73 m²
No history of angioedema (absolute contraindication)

Initiation Protocol

ACE Inhibitor Washout Period

If switching from an ACE inhibitor, you must allow a 36-hour washout period between the last ACE inhibitor dose and the first ARNI dose to prevent angioedema risk 2, 4. This washout is not required when switching from an ARB 5.

Starting Dose Strategy

The approach differs based on prior RAS inhibitor exposure 4:

For patients on adequate doses of ACE inhibitor or ARB:

Start sacubitril/valsartan 49/51 mg twice daily
This is the standard starting dose for most patients

For patients NOT on ACE inhibitor/ARB or on low doses:

Start at half the usual dose: 24/26 mg twice daily
This reduces risk of hypotension and other adverse effects
Then follow standard titration schedule

In-Hospital Initiation

Patients hospitalized with acute decompensated HFrEF should be switched to ARNI before discharge when stabilized 5, 2. The PIONEER-HF trial demonstrated that in-hospital initiation is safe and results in greater NT-proBNP reduction and lower subsequent hospitalization rates compared to delayed initiation 5.

For ACE inhibitor users admitted to hospital: discontinue the ACE inhibitor at admission, enabling ARNI prescription 36 hours later before discharge 5.

Titration Schedule

Double the dose every 2-4 weeks to reach the target maintenance dose of 97/103 mg twice daily, as tolerated 4. The key principle is that low doses provide substantial benefit—achieving low doses of all foundational therapies takes precedence over reaching target doses 6.

Titration timeline:

Week 0: 49/51 mg twice daily (or 24/26 mg if RAS-naïve)
Week 2-4: 97/103 mg twice daily (target dose)

Monitoring Requirements

Check the following parameters 1-2 weeks after each dose increment, at 3 months, then every 6 months 3, 7:

Blood pressure (supine and standing to detect orthostatic hypotension)
Serum creatinine and eGFR
Serum potassium

Acceptable Changes During Initiation

Creatinine increase up to 30% is expected and acceptable if it stabilizes 7, 8
Symptomatic hypotension may occur—separate ARNI dosing from other blood pressure medications if this persists 7
Consider reducing diuretic dose if patient is otherwise stable before reducing ARNI dose 7

Contraindications

Absolute contraindications 2, 4:

History of angioedema (with any medication)
Concomitant ACE inhibitor use
Pregnancy or planned pregnancy

Relative contraindications requiring caution:

Symptomatic hypotension despite medication adjustment
Serum potassium ≥5.2 mmol/L
eGFR <30 mL/min/1.73 m²
Severe hepatic impairment

Common Adverse Effects and Management

Hypotension (most common) 1, 2:

Occurs more frequently than with ACE inhibitors but is manageable
Separate timing of ARNI from other antihypertensive medications
Reduce diuretic dose if volume status permits
Reduce dose of other vasodilators (nitrates) if no longer needed
If persistent, reduce ARNI dose rather than discontinue

Hyperkalemia 3:

Monitor closely, especially when combined with mineralocorticoid receptor antagonist
Avoid potassium-sparing diuretics during initiation
Avoid NSAIDs

Worsening renal function 3:

Up to 30% increase in creatinine is acceptable
If >30% increase or eGFR drops significantly, hold dose and reassess
Ensure adequate hydration; avoid excessive diuresis

Angioedema 1, 2:

Rare (<1%) but serious
More common in Black patients and women
If occurs, discontinue immediately and do not rechallenge

Priority in Treatment Sequence

The 2022 AHA/ACC/HFSA guidelines and recent evidence support rapid sequencing of all four foundational therapies (ARNI, beta-blocker, MRA, SGLT2 inhibitor) within 2-4 weeks rather than the traditional slow sequential approach 2, 6.

A practical accelerated sequence 6:

Week 0: Start beta-blocker + SGLT2 inhibitor simultaneously
Week 1-2: Add ARNI (after ACE inhibitor washout if applicable)
Week 2-4: Add mineralocorticoid receptor antagonist

This approach recognizes that drugs act rapidly to reduce morbidity and mortality, and the efficacy of each is independent of the others 6.

Special Populations

De novo heart failure (newly diagnosed): ARNI can be initiated as first-line therapy without prior ACE inhibitor/ARB exposure 5, 2. The PIONEER-HF trial showed this is safe and effective, with one-third of enrolled patients having no prior HF history 5.

Patients with EF 41-49% (HFmrEF): ARNI may be considered, particularly in those with LVEF on the lower end of this spectrum, though evidence is less robust 9, 10.

Critical Implementation Points

Do not combine ARNI with ACE inhibitors or direct renin inhibitors (increased angioedema risk) 11, 2
Do not routinely combine with ARBs (valsartan is already in the formulation) 11
Continue ARNI even if symptoms improve or EF recovers to prevent relapse 9
Avoid abrupt withdrawal—if dose reduction needed, decrease by half rather than discontinue 7

The evidence strongly supports ARNI as superior to ACE inhibitors for reducing both mortality and morbidity in HFrEF, with the PARADIGM-HF trial showing consistent benefits across all prespecified subgroups 1, 2. The 2022 guidelines elevated ARNI to Class I recommendation as the preferred RAS inhibitor for symptomatic HFrEF 2.

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