What is the initial management for patients with reduced ejection fraction, specifically those with heart failure with reduced ejection fraction (HFrEF)?

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

Start all four core medication classes simultaneously at low doses within the first 4-6 weeks of diagnosis: SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRAs), beta-blockers, and sacubitril/valsartan (or ACE inhibitors if not tolerated), beginning with SGLT2 inhibitors and MRAs first as they have minimal blood pressure effects. 1, 2, 3

The Four Pillars of HFrEF Therapy

First Priority: SGLT2 Inhibitors and MRAs (Start These First)

• SGLT2 inhibitors (empagliflozin or dapagliflozin) should be initiated immediately as they provide rapid benefits within weeks, require no dose titration, have minimal effect on blood pressure, and work independently of other medications 1, 2, 3
• Empagliflozin can be used with eGFR ≥30 ml/min/1.73 m², while dapagliflozin can be used with eGFR ≥20 ml/min/1.73 m² 2, 3
• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be started concurrently as they also have minimal BP-lowering effects and reduce mortality by at least 20% in symptomatic patients with LVEF ≤35% 1, 2, 3

Second Priority: Beta-Blockers

• Start a low-dose beta-blocker if heart rate >70 bpm, using carvedilol, metoprolol succinate, or bisoprolol—these are the only beta-blockers proven to prolong life 1, 2, 3
• Selective β₁ receptor blockers (metoprolol succinate or bisoprolol) may be preferred in patients with borderline blood pressure due to lesser BP-lowering effects compared to carvedilol, which has combined α₁, β₁, and β₂-blocking properties 1
• Beta-blockers reduce the risk of sudden death and should not be delayed even in clinically stable patients 1

Third Priority: Renin-Angiotensin System Inhibition

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors for patients with NYHA class II-III symptoms, starting at very low dose (25 mg twice daily) or low dose (50 mg twice daily) 1, 2, 3
• Sacubitril/valsartan reduces mortality by at least 20% and reduces the risk of sudden death, making it superior to ACE inhibitors which only provide 5-16% mortality reduction 1
• ACE inhibitors (or ARBs if ACE inhibitor intolerant) should be used only if sacubitril/valsartan is not tolerated due to hypotension 1

Implementation Strategy: The Simultaneous Approach

Step 1: Initial Assessment (Before Starting Medications)

• Measure blood pressure (both supine and standing) to assess for orthostatic hypotension 3
• Check heart rate to guide beta-blocker and ivabradine use 3
• Evaluate renal function (eGFR and serum creatinine) to guide medication dosing 3
• Assess volume status to guide diuretic therapy 1, 3
• Perform transthoracic echocardiography to confirm LVEF and assess for device therapy eligibility 3

Step 2: Medication Initiation Based on Blood Pressure

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

• Start SGLT2 inhibitor and MRA immediately 2, 3
• Add low-dose beta-blocker if heart rate >70 bpm 1, 2
• Add low-dose sacubitril/valsartan (25-50 mg twice daily) 1, 2, 3
• Adjust diuretics according to volume status to avoid overdiuresis 1, 2

For patients with low blood pressure (SBP <100 mmHg but asymptomatic or mildly symptomatic):

• Do not withhold guideline-directed medical therapy (GDMT) 1, 3
• Discontinue non-HF hypotensive medications (antihypertensives, alpha-blockers for benign prostatic hypertrophy) 1
• Start SGLT2 inhibitor and MRA first as they have minimal BP-lowering effects 1, 2, 3
• Use very low starting doses of sacubitril/valsartan (25 mg twice daily) or consider low-dose ACE inhibitor instead 1
• Consider ivabradine if beta-blockers are not tolerated hemodynamically, either alone or with low-dose beta-blockers 1, 4

Step 3: Dose Titration

• Up-titrate one medication at a time using small increments every 1-2 weeks until target or maximally tolerated doses are achieved 1, 2, 3
• Close monitoring of blood pressure, heart rate, renal function, and potassium is essential during titration 3
• Even lower-than-target doses provide significant benefits, so do not abandon therapy if target doses cannot be reached 2

Diuretic Management

• Diuretics should be used as needed for congestion but adjusted according to volume status to avoid overdiuresis which can lead to hypotension and impair tolerance of other HF medications 1, 2
• Loop diuretics are preferred for treatment of congestion in symptomatic patients, though they are less effective than thiazide diuretics in lowering blood pressure 1
• Thiazide or thiazide-like diuretics can be useful for blood pressure control and to reverse mild volume overload 1

Device Therapy Considerations

• ICD implantation is recommended for primary prevention in patients with LVEF ≤35%, NYHA class II-III symptoms, and ≥3 months of optimal medical therapy, provided life expectancy >1 year with good functional status 1, 3
• Wait at least 40 days post-myocardial infarction before ICD implantation 3
• Cardiac resynchronization therapy (CRT) is recommended for symptomatic patients with LVEF ≤35%, sinus rhythm, and QRS duration ≥150 ms with left bundle branch block morphology 1, 3

Special Situations

Managing Symptomatic Hypotension

• Transient dizziness upon standing is typically manageable through patient education without necessitating reduction in HF pharmacotherapy 1
• If systolic BP <80 mmHg with significant orthostatic hypotension, fatigue, or dizziness, reassess volume status and consider decreasing diuretics first 1
• Symptomatic hypotension in chronic HFrEF does not always indicate poor tolerance to HF drugs 1

Alternative Heart Rate Control

• If beta-blockers cannot be tolerated and patient is in sinus rhythm, ivabradine may be used to reduce the risk of hospitalization for worsening heart failure 1, 4
• Ivabradine helps facilitate beta-blocker titration when used in combination with low-dose beta-blockers 1
• In atrial fibrillation with uncontrolled heart rate, digoxin may be used 1

Critical Pitfalls to Avoid

• Never use the traditional step-by-step approach that delays one drug class until another is optimized—this delays the benefits of comprehensive therapy 2, 3
• Do not discontinue GDMT for asymptomatic hypotension or mild renal function changes during hospitalization or follow-up 2
• Avoid excessive diuresis as it can lead to hypotension and impair tolerance of other HF medications 1, 2
• Never combine ACE inhibitors with ARBs, and avoid combining ACE inhibitors or ARBs with MRAs without close monitoring 3
• Never use diltiazem or verapamil (non-dihydropyridine calcium channel blockers) in HFrEF patients as they worsen survival 1
• Avoid alpha-adrenergic blockers (such as doxazosin) and moxonidine as they may worsen outcomes 1
• Adjust medications based on clinical response, with one drug at a time, to identify the source of any adverse effects 2

Medications to Avoid

• Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) are contraindicated 1
• Moxonidine is contraindicated 1
• Alpha-adrenergic blockers should be avoided unless other drugs are inadequate at maximum tolerated doses 1