What is the role of Angiotensin-Receptor Neprilysin Inhibitors (ARNI) in the management of acute heart failure?

ARNI in Acute Heart Failure

ARNI (sacubitril/valsartan) should be initiated in hospitalized patients with acute decompensated heart failure and reduced ejection fraction (HFrEF) before discharge, as it reduces NT-proBNP levels, improves cardiac remodeling, and decreases rehospitalization without increased safety concerns compared to ACE inhibitors. 1

Evidence for ARNI Initiation in Acute Heart Failure

Timing of Initiation

• The 2022 AHA/ACC/HFSA guidelines recommend ARNI as de novo treatment in hospitalized patients with acute HF before discharge (Class I recommendation), based on improvements in health status, reduction in NT-proBNP, and improved left ventricular remodeling parameters compared to ACEi/ARB. 1

• The PIONEER-HF trial demonstrated that ARNI initiated after hemodynamic stabilization in acute decompensated HF reduced NT-proBNP levels without increased rates of adverse events (worsening renal function, hyperkalemia, symptomatic hypotension, angioedema) when compared with enalapril. 1

• The TRANSITION trial showed that early initiation of ARNI either before or after discharge had similar safety outcomes, suggesting that early initiation simplifies management rather than requiring initial ACEi uptitration followed by switching. 1

Clinical Outcomes in Acute HF

• Real-world data from hospitalized acute decompensated HF patients showed that ARNI initiation after hemodynamic stabilization resulted in 48.9% of patients achieving absolute LVEF increase >5% versus 25.2% with ACEi (P=0.001). 2

• All-cause mortality was significantly lower with ARNI (5.7%) compared to ACEi (15.3%, P=0.038) in acute decompensated HF patients. 2

• Rehospitalization for heart failure was reduced from 71% with ACEi to 50% with ARNI (P=0.002) in the acute HF setting. 2

• In patients with newly diagnosed heart failure at acute presentation, ARNI showed even more dramatic benefits: 30% achieved LVEF >50% versus 6.5% with ACEi (P=0.017), and rehospitalization was reduced from 73.3% to 23.3% (P<0.01). 2

Practical Implementation Algorithm

Step 1: Confirm Patient Eligibility

• HFrEF with LVEF ≤40% 1
• NYHA class II-III symptoms (or acute decompensation) 1
• Hemodynamically stable (systolic BP >100 mmHg, no vasopressor requirement) 2
• No history of angioedema (Class 3: Harm contraindication) 1

Step 2: Timing Considerations

• Initiate after hemodynamic stabilization during hospitalization for acute HF, typically when:
  • Systolic blood pressure stable >100 mmHg 2
  • No intravenous vasodilators or inotropes for at least 6 hours 1
  • Adequate renal function (creatinine stable) 2

Step 3: Washout Requirements

• If switching from ACEi: mandatory 36-hour washout period (Class 3: Harm if not observed) 1
• If switching from ARB: no washout required 3
• If treatment-naïve: can initiate directly 1

Step 4: Dosing Strategy

• Start with 24/26 mg twice daily if:

  • Previously on low-dose ACEi/ARB 3
  • Systolic BP 100-110 mmHg 4
  • Elderly or frail patients 4

• Start with 49/51 mg twice daily if:

  • Previously on valsartan ≥160 mg daily equivalent 3
  • Systolic BP >110 mmHg 4
  • Younger, robust patients 4

• Target dose: 97/103 mg twice daily (titrate every 2-4 weeks as tolerated) 1

Step 5: Monitoring Parameters

• Blood pressure at each dose increase (hold if systolic <90 mmHg) 4, 2
• Serum creatinine and potassium within 1-2 weeks of initiation and dose changes 4, 2
• NT-proBNP levels to assess treatment response (expect 40-50% reduction by 12 weeks) 4

Critical Safety Considerations

Absolute Contraindications

• History of angioedema with any agent (Class 3: Harm) 1
• Concomitant ACEi use or <36 hours since last ACEi dose (Class 3: Harm) 1
• Pregnancy or planned pregnancy 4

Relative Contraindications Requiring Caution

• Systolic blood pressure <100 mmHg (increased hypotension risk) 4, 2
• Serum potassium >5.0 mEq/L (monitor closely) 1
• Significant renal impairment (eGFR <30 mL/min requires dose adjustment) 4
• Bilateral renal artery stenosis 1

Common Pitfalls to Avoid

Do not combine ARNI with ARB - sacubitril/valsartan already contains valsartan (an ARB), making additional ARB therapy unnecessary and potentially harmful due to increased hypotension risk. 3

Do not add ACEi to ARNI - this combination increases angioedema risk and other complications (hypotension, renal insufficiency). 1

Do not underdose - aim for target doses shown in clinical trials (97/103 mg twice daily); intermediate doses are acceptable if target not tolerated, but avoid remaining on starting doses long-term. 3

Do not delay initiation - early initiation in the acute HF hospitalization (after stabilization) provides greater benefit than delayed outpatient initiation, particularly for newly diagnosed HF. 2, 5

Superiority Over Traditional RAS Inhibition

• ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril in the PARADIGM-HF trial. 1

• The benefit was consistent across both death and HF hospitalization endpoints individually. 1

• ARNI provides high economic value compared to ACEi in chronic symptomatic HFrEF (Class I, High Value recommendation). 1

• Real-world data confirmed superiority: hazard ratio 0.74 (95% CI 0.57-0.96) for composite cardiovascular death and HF hospitalization versus ARB therapy. 6

Special Population: Acute MI with LV Dysfunction

• For acute MI patients with LVEF ≤40%, ACEi remains the standard recommendation within the first 24 hours (Class I, Level A). 1

• ARNI can be considered as replacement therapy after initial stabilization if patient tolerates ACEi/ARB, but the PARADISE-MI trial data on early post-MI ARNI use showed uncertain efficacy in this specific timeframe. 1

• The 36-hour washout from ACEi must be strictly observed before initiating ARNI in post-MI patients. 1