What are the management options for Heart Failure with Reduced Ejection Fraction (HFrEF)?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should be started on four core medication classes simultaneously at low doses and titrated gradually: SGLT2 inhibitors, ARNi (or ACEi/ARB if ARNi not feasible), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). 1, 2, 3

Initial Diagnostic Evaluation

Before initiating therapy, obtain the following essential tests:

• Transthoracic echocardiography to confirm reduced ejection fraction (LVEF ≤40%) and assess for structural abnormalities 4
• Blood pressure measurement (supine and standing) to assess for orthostatic hypotension 4
• Heart rate assessment to guide beta-blocker and ivabradine use 4
• Renal function (eGFR and serum creatinine) and serum potassium to guide medication dosing and safety 1, 4
• Volume status assessment to guide diuretic therapy 2, 4
• Evaluation for underlying causes including coronary artery disease, hypertension, and valvular disease 4

Core Pharmacologic Therapy: The Four Pillars

1. SGLT2 Inhibitors (Start First)

Begin with empagliflozin 10 mg daily or dapagliflozin 10 mg daily immediately as these agents have minimal blood pressure effects, provide rapid benefits within weeks, require no dose titration, and work independently of other medications. 1, 2, 3

• Empagliflozin can be used with eGFR ≥30 mL/min/1.73 m² 2
• Dapagliflozin can be used with eGFR ≥20 mL/min/1.73 m² 2
• These agents reduce cardiovascular mortality and heart failure hospitalizations 3

2. Mineralocorticoid Receptor Antagonists (Start Concurrently with SGLT2i)

Initiate spironolactone 12.5-25 mg daily or eplerenone 25 mg daily in patients with LVEF ≤35% and NYHA class II-IV symptoms, provided eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L. 1, 3

• Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 3
• MRAs have minimal blood pressure effects, making them ideal for early initiation 2, 4
• Monitor potassium and renal function 2-3 days after initiation, then monthly for 3 months, then every 3 months thereafter 3

3. Beta-Blockers (Add After SGLT2i and MRA if Heart Rate >70 bpm)

Use one of three evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol starting at low doses and titrating to target. 1, 3

• Target doses: bisoprolol 10 mg once daily, carvedilol 25-50 mg twice daily, or metoprolol succinate 200 mg daily 3
• Selective β₁ receptor blockers (bisoprolol, metoprolol) may be preferred in patients with borderline blood pressure due to lesser BP-lowering effects 2, 4
• These agents reduce mortality, sudden death, and hospitalizations 1

4. ARNi (Preferred) or ACEi/ARB

Sacubitril/valsartan (ARNi) is recommended over ACE inhibitors for patients with NYHA class II-III symptoms. 1, 3

• Start with low dose: 24/26 mg or 49/51 mg twice daily 3, 5
• Target dose: 97/103 mg twice daily 3
• ARNi reduces morbidity and mortality more effectively than ACE inhibitors 1
• If ARNi is not feasible due to cost or hypotension, use ACE inhibitors (enalapril, lisinopril, ramipril) 1
• If ACE inhibitor causes cough or angioedema, use ARB (candesartan or valsartan) 1

Implementation Strategy Based on Blood Pressure

For Patients with Adequate Blood Pressure (SBP ≥100 mmHg):

1. Start SGLT2 inhibitor and MRA immediately 2, 4
2. Add low-dose beta-blocker if heart rate >70 bpm 2, 4
3. Add low-dose ARNi (or ACEi/ARB if ARNi not feasible) 2, 4
4. Titrate one medication at a time using small increments until target or maximally tolerated doses are achieved 4

For Patients with Low Blood Pressure (SBP <100 mmHg):

Do not withhold guideline-directed medical therapy if the patient is asymptomatic or has adequate organ perfusion. 4

1. Discontinue non-heart failure hypotensive medications 4
2. Start with SGLT2 inhibitor and MRA as they have minimal BP-lowering effects 2, 4
3. Use very low starting doses of sacubitril/valsartan (24/26 mg twice daily) or ACE inhibitors 4
4. Consider ivabradine if beta-blockers are not tolerated hemodynamically 4
5. Adjust diuretics to avoid overdiuresis which can worsen hypotension 2, 4

Diuretic Management

Use loop diuretics as needed for congestion, but adjust according to volume status to avoid overdiuresis. 2, 4

• Excessive diuresis leads to hypotension and impairs tolerance of other HF medications 2
• Loop diuretics are preferred over thiazide diuretics for symptom control 6
• Diuretic doses may need adjustment when initiating or titrating GDMT 3

Additional Therapies for Specific Indications

Ivabradine

Consider ivabradine 2.5-5 mg twice daily for patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy. 3, 7

Hydralazine-Isosorbide Dinitrate

Add this combination in self-identified African American patients with NYHA class III-IV symptoms despite optimal therapy with other GDMT. 3, 7

Device Therapy Evaluation

Implantable Cardioverter-Defibrillator (ICD)

ICD is recommended for primary prevention in patients with LVEF ≤35% despite ≥3 months of optimal medical therapy, NYHA class II-III symptoms, and expected survival >1 year with good functional status. 4, 3

• Wait at least 40 days post-myocardial infarction before ICD implantation 4

Cardiac Resynchronization Therapy (CRT)

CRT is indicated for symptomatic patients with LVEF ≤35%, sinus rhythm, left bundle branch block with QRS duration ≥150 ms, and NYHA class II-IV symptoms despite optimal therapy. 4, 3

Special Population: HFrEF with Improved Ejection Fraction (HFimpEF)

Patients with previous HFrEF who improve their LVEF to >40% should continue their HFrEF treatment regimen. 1, 3

Critical Pitfalls to Avoid

• Do not use the traditional step-by-step approach that delays one drug class until another is optimized—this delays the benefits of comprehensive therapy 2, 4
• Do not discontinue GDMT for asymptomatic hypotension or mild renal function changes during hospitalization 2, 3
• Do not over-diurese—excessive diuresis causes hypotension and impairs tolerance of other medications 2, 4
• Never combine ACE inhibitors with ARBs and MRAs due to increased risk of hyperkalemia and renal dysfunction 4
• Never use diltiazem or verapamil in HFrEF patients as they worsen outcomes 4
• Do not be overly cautious with dosing—even lower-than-target doses provide significant benefits, but aim for target doses when possible 2

Monitoring During Titration

Monitor blood pressure, heart rate, renal function (eGFR, creatinine), and potassium closely during medication titration. 1, 4, 3

• Adjust one medication at a time to identify the source of any adverse effects 2
• Continue GDMT even with mild decreases in renal function or asymptomatic blood pressure reduction 2, 3

Hospitalized Patients

In patients with HFrEF requiring hospitalization, GDMT should be initiated during hospitalization after clinical stability is achieved, and preexisting GDMT should be continued and optimized unless contraindicated. 2

• Continuation or initiation of GDMT in hospitalized patients is associated with lower risk of post-discharge death and readmission 2