What is the recommended initial management for heart failure with reduced ejection fraction (HFrEF)?

Initial Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

Start all four foundational medication classes simultaneously at low doses as soon as possible after diagnosis: SGLT2 inhibitor, mineralocorticoid receptor antagonist (MRA), beta-blocker, and either an ARNI (sacubitril/valsartan) or ACE inhibitor, with ARNI being the preferred choice. 1, 2, 3

Core Four-Pillar Pharmacotherapy

The modern approach to HFrEF management has evolved from sequential medication initiation to rapid implementation of all four medication classes together. This strategy maximizes early mortality and morbidity benefits rather than delaying therapy with traditional step-wise approaches. 1, 2

Sequencing Strategy Based on Blood Pressure

For patients with adequate blood pressure (SBP ≥100 mmHg):

• Start SGLT2 inhibitor (dapagliflozin or empagliflozin) and MRA (spironolactone or eplerenone) first as these have minimal blood pressure-lowering effects but provide rapid benefits 2
• Add low-dose beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) if heart rate >70 bpm 1, 2
• Add low-dose ARNI (sacubitril/valsartan 24/26 mg or 49/51 mg twice daily) as the preferred renin-angiotensin system inhibitor over ACE inhibitors, as it provides superior mortality reduction of at least 20% 1, 4

For patients with low blood pressure (SBP <100 mmHg):

• Begin with SGLT2 inhibitor and MRA only as they have minimal BP-lowering effects 2
• Reduce diuretic doses first to avoid overdiuresis which impairs tolerance of other medications 2, 3
• Consider very low starting doses of beta-blocker and ARNI once volume status is optimized 2

Specific Medication Details

SGLT2 Inhibitors:

• Effective even with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 2
• Provide rapid benefits and should be started early 2

Mineralocorticoid Receptor Antagonists:

• Indicated for patients with LVEF ≤35% and symptomatic HF 1, 2
• Provide at least 20% mortality reduction and reduce sudden cardiac death 1
• Require monitoring of renal function and serum potassium (serum creatinine should be ≤2.5 mg/dL in men and ≤2.0 mg/dL in women; serum potassium should be <5.0 mEq/L) 1, 5

Beta-Blockers:

• Use carvedilol, metoprolol succinate, or bisoprolol 1, 3
• Reduce mortality by at least 20% and decrease sudden cardiac death 1
• Start at low doses and titrate every 2 weeks to target doses 3

ARNI (Sacubitril/Valsartan):

• Preferred over ACE inhibitors for symptomatic patients, providing superior mortality reduction 1
• Starting dose: 24/26 mg or 49/51 mg twice daily, titrating to target of 97/103 mg twice daily 4
• Requires 36-hour washout period if switching from an ACE inhibitor to avoid angioedema risk 6, 4
• Contraindicated with concomitant ACE inhibitor use 4

ACE Inhibitors (if ARNI not feasible):

• Use enalapril (starting 2.5 mg twice daily), lisinopril (starting 5 mg daily), or equivalent 3, 7
• Reduce morbidity and mortality in HFrEF 6, 7
• Titrate every 2 weeks to target doses 3

Titration Strategy

• Titrate all medications gradually every 2-4 weeks to target or maximum tolerated doses 3, 4
• Adjust one medication at a time to identify the source of any adverse effects 2
• Even lower-than-target doses provide significant benefits, so don't withhold therapy due to inability to reach full target doses 2

Managing Common Barriers

Symptomatic Hypotension:

• Reduce diuretic dose first rather than reducing guideline-directed medical therapy (GDMT) 3
• Asymptomatic hypotension is expected and beneficial with GDMT 3

Hyperkalemia:

• Adjust MRA dose and use potassium binders rather than discontinuing ARNI or beta-blocker 3
• This allows continuation of life-saving therapy 3

Mild Renal Function Decrease:

• Do not routinely discontinue GDMT during mild, asymptomatic renal function changes 2
• Monitor closely but continue therapy unless significant deterioration occurs 2

Diuretic Management

• Use diuretics as needed for congestion but adjust according to volume status 2
• Avoid overdiuresis which leads to hypotension and impairs tolerance of other HF medications 2
• Evaluate volume status before each medication adjustment 2

Critical Pitfalls to Avoid

• Do not use the traditional step-by-step approach that delays benefits of comprehensive therapy 2
• Do not be overly cautious with dosing - even partial doses provide significant benefits 2
• Do not discontinue GDMT during hospitalization unless absolutely contraindicated, as continuation is associated with lower risk of post-discharge death and readmission 2, 3
• Avoid diltiazem or verapamil as they increase risk of worsening heart failure and hospitalization 1
• Do not combine ARB with both ACE inhibitor and MRA due to increased risk of renal dysfunction and hyperkalemia 1