Role of ARNI in Heart Failure
ARNI (sacubitril/valsartan) is now the preferred first-line renin-angiotensin system inhibitor for all patients with symptomatic HFrEF and should replace ACE inhibitors or ARBs to reduce cardiovascular death and heart failure hospitalization. 1
Primary Indication and Evidence
ARNI is FDA-approved and guideline-recommended to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure and reduced ejection fraction. 2
- The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril, with benefits seen equally for both death and hospitalization. 1
- This mortality and morbidity benefit represents a Class I, Level of Evidence B-R recommendation from ACC/AHA/HFSA guidelines. 1
When to Initiate ARNI
ARNI should be initiated in patients with NYHA Class II or III symptoms who tolerate an ACE inhibitor or ARB, replacing these agents to further reduce morbidity and mortality. 1
Specific Clinical Scenarios:
- De novo initiation: ARNI can be started as first-line therapy in newly diagnosed HFrEF patients to simplify management, though this approach has limited data compared to switching from ACE inhibitors/ARBs. 1
- Hospitalized patients: ARNI is recommended before discharge in patients hospitalized with acute decompensated HF, as the PIONEER-HF trial showed reduced NT-proBNP levels, improved health status, and better LV remodeling without increased adverse events compared to enalapril. 1
- Stable outpatients: For chronic symptomatic HFrEF patients already on ACE inhibitors or ARBs, switching to ARNI is strongly recommended. 1, 3
Integration with Guideline-Directed Medical Therapy
ARNI should be initiated as part of a four-pillar foundational therapy approach that includes a beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor. 3
- Start ARNI (or ACE inhibitor if ARNI unavailable) plus beta-blocker simultaneously. 3
- Add SGLT2 inhibitor early, as it requires no titration. 3
- Add MRA when LVEF remains ≤35% or symptoms persist despite ARNI and beta-blocker therapy. 3
- This combination strategy provides high economic value for reducing morbidity and mortality. 1
Dosing and Titration
The recommended starting dose is 49/51 mg twice daily, with a target maintenance dose of 97/103 mg twice daily. 2
- Titrate every 2-4 weeks, doubling the dose at each step until target dose is achieved or maximum tolerated dose is reached. 3, 2
- For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or moderate hepatic impairment (Child-Pugh B), reduce starting dose to 24/26 mg twice daily. 2
- Real-world data from Taiwan showed that 41.6% of patients received less than half the standard dose at 12 months, yet still demonstrated safety and effectiveness with improved LVEF and reduced BNP. 4
Critical Safety Considerations and Contraindications
ARNI is absolutely contraindicated in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy, and must not be administered concomitantly with ACE inhibitors or within 36 hours of the last ACE inhibitor dose. 1, 2
Additional Contraindications:
- Hypersensitivity to any component. 2
- Concomitant use with aliskiren in patients with diabetes. 2
- Pregnancy (causes fetal toxicity). 2
Important Cautions:
- Monitor for symptomatic hypotension, particularly in volume-depleted patients or those with systolic BP <100 mm Hg. 1, 2
- Check serum creatinine/eGFR and potassium within 1-2 weeks after initiation or dose increases. 3
- Observe for signs of angioedema, though incidence is comparable to enalapril (<1%). 1
- Use caution in patients with renal insufficiency or elevated serum potassium (>5.0 mEq/L). 1
Monitoring Parameters
Check blood pressure, serum creatinine/eGFR, and serum potassium within 1-2 weeks after initiating or increasing ARNI doses. 3
- Real-world data demonstrates that renal function remains stable (serum creatinine 1.7-1.8 mg/dL, p=0.091) after 12 months of ARNI therapy, even in patients with higher baseline creatinine than PARADIGM-HF populations. 4
- Monitor for clinical improvement: LVEF typically improves (30.8% to 36.8%, p<0.001) and BNP decreases (777.0 to 655.8 pg/mL, p=0.032) within 12 months. 4
- P-wave dispersion and maximum P-wave duration decrease within 1 month, correlating with clinical improvement and reduced NT-proBNP levels. 5
Common Pitfalls to Avoid
The most critical error is failing to observe the mandatory 36-hour washout period between discontinuing an ACE inhibitor and starting ARNI, which significantly increases angioedema risk. 1, 2
- Do not add ACE inhibitors to patients already on ARNI, as this increases risk of angioedema and other complications. 1
- Do not discontinue ARNI in patients whose LVEF improves to >40%—continue guideline-directed medical therapy regardless of improved ejection fraction. 3
- Barriers to ARNI prescription include practitioner unfamiliarity, safety concerns, and payer reimbursement issues, but these should not prevent eligible patients from receiving this superior therapy. 6
- A pharmacist-led ARNI initiation and titration program achieves target doses in 60.9% of patients versus only 18.0% with usual care, suggesting that structured protocols improve outcomes. 7
Alternatives When ARNI is Not Accessible
If ARNI is not accessible due to payer coverage or cost issues, ACE inhibitors or ARBs should be used to reduce morbidity and mortality in HFrEF patients. 1
- ACE inhibitors remain Class I, Level of Evidence A for reducing morbidity and mortality in HFrEF. 1
- ARBs are recommended for patients intolerant to ACE inhibitors due to cough or angioedema. 1
- However, ARNI remains the preferred agent when accessible, as it has been found superior to ACE inhibitors. 1