What are the initial medication recommendations for patients with Heart Failure with Reduced Ejection Fraction (HFrEF)?

Initial Medication Recommendations for HFrEF

For patients with heart failure with reduced ejection fraction (HFrEF), initiate four foundational medications simultaneously at low doses: an ARNI (sacubitril/valsartan preferred) or ACE inhibitor, a beta-blocker (bisoprolol, carvedilol, or metoprolol succinate), a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, then titrate to target doses over 6-12 weeks. 1, 2

The Four-Pillar Approach to HFrEF Treatment

The 2022 ACC/AHA/HFSA guidelines establish that guideline-directed medical therapy (GDMT) now includes four medication classes that should be started together rather than sequentially 1:

1. Renin-Angiotensin System Inhibition

First-line choice: ARNI (Sacubitril/Valsartan)

• ARNI is recommended as the preferred RAS inhibitor for patients with NYHA class II-III HFrEF to reduce morbidity and mortality (Class I, Level A) 1
• Start at 49/51 mg twice daily for most patients, or 24/26 mg twice daily if previously on low-dose ACE inhibitor/ARB, elderly (≥75 years), severe renal impairment, or moderate hepatic impairment 3
• Target dose: 97/103 mg twice daily, doubling every 2-4 weeks as tolerated 1, 3
• Sacubitril/valsartan demonstrated superior reduction in cardiovascular death and HF hospitalization compared to enalapril (HR 0.80, p<0.0001) and improved all-cause mortality (HR 0.84, p=0.0009) 3

Alternative: ACE Inhibitor

• Use ACE inhibitors when ARNI is not feasible (Class I, Level A) 1
• If switching from ACE inhibitor to ARNI, a mandatory 36-hour washout period is required to avoid angioedema 3

Second alternative: ARB

• Use ARBs only if intolerant to ACE inhibitors due to cough or angioedema AND ARNI is not feasible (Class I, Level A) 1

2. Beta-Blockers

Use one of three evidence-based beta-blockers: bisoprolol, carvedilol, or sustained-release metoprolol succinate (Class I, Level A) 1, 4

• These specific agents have proven mortality reduction in HFrEF 1
• Start at low doses and titrate to maximally tolerated target doses 1, 2
• Indicated for all patients with current or prior HFrEF symptoms unless contraindicated 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

Add spironolactone or eplerenone for patients with NYHA class II-IV symptoms (Class I, Level A) 1

• Required criteria: eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L 1
• Careful monitoring of potassium and renal function is mandatory at initiation and closely thereafter to minimize hyperkalemia and renal insufficiency risk 1
• Contraindicated if creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), or potassium >5.0 mEq/L 1

4. SGLT2 Inhibitors

SGLT2 inhibitors (dapagliflozin or empagliflozin) are recommended for all symptomatic chronic HFrEF patients to reduce HF hospitalization and cardiovascular mortality, regardless of diabetes status (Class I, Level A) 1, 2

• This represents a major advancement in HFrEF therapy with benefits independent of glycemic control 1, 5

Implementation Strategy

Start all four medication classes simultaneously at initial low doses rather than waiting to achieve target dosing before initiating the next medication 1, 2

• This approach is supported by the most recent guidelines and represents a paradigm shift from sequential therapy 1, 2
• Titrate medications to target doses over 6-12 weeks as tolerated 2
• Sequence can be guided by clinical factors if simultaneous initiation is not feasible, but avoid unnecessary delays 1

Additional Essential Therapies

Diuretics

Use loop diuretics for patients with fluid retention and congestion 1, 2

• Furosemide 20-40 mg once or twice daily initially (maximum 600 mg/day) 1
• Torsemide 10-20 mg once daily (maximum 200 mg/day) with longer duration of action 1
• Bumetanide 0.5-1.0 mg once or twice daily (maximum 10 mg/day) 1
• Diuretics provide symptom relief but do not reduce mortality 1, 2

Hydralazine-Isosorbide Dinitrate

Add hydralazine-isosorbide dinitrate for self-described African American patients with NYHA class II-IV HF already on ACE inhibitors, beta-blockers, and diuretics 1

Critical Monitoring Parameters

Regular assessment must include: 2

• Symptoms and functional capacity
• Blood pressure and heart rate
• Renal function (creatinine, eGFR)
• Electrolytes (particularly potassium with MRAs)
• Volume status

Common Pitfalls to Avoid

Do not underdose or fail to titrate medications to target doses 2

• Asymptomatic hypotension or mild laboratory changes should not prevent titration to target doses 2
• Medium-range doses do not provide most of the benefits—target doses are necessary 2

Avoid inappropriate medication combinations: 1

• Routine triple combination of ACE inhibitor + ARB + aldosterone antagonist is potentially harmful 1
• NSAIDs should be avoided as they worsen renal function and counteract GDMT benefits 2

Do not discontinue medications inappropriately 2

• Temporary dose reductions are preferable to permanent discontinuation 2
• 40% of patients requiring temporary dose reduction can be restored to target doses 2

Monitor for hyperkalemia with MRAs 1

• Inappropriate use when creatinine or potassium levels exceed thresholds is potentially harmful and life-threatening 1