What is the initial treatment approach for a patient with Heart Failure with Reduced Ejection Fraction (HFrEF)?

Initial Treatment Approach for HFrEF

Start all four foundational medication classes simultaneously at low doses immediately upon diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (sacubitril/valsartan preferred over ACE inhibitor/ARB), plus loop diuretics for volume management. 1, 2

Confirm Diagnosis First

Before initiating therapy, document:

• LVEF ≤40% via transthoracic echocardiography 3
• Symptomatic heart failure (NYHA Class II-IV) 4
• Baseline vital signs: blood pressure, heart rate 3
• Laboratory values: renal function (eGFR), potassium, sodium 3
• Volume status: presence of edema, jugular venous distension, pulmonary rales 1

The Quadruple Therapy Regimen

Start These Four Medications Simultaneously (Not Sequentially)

1. SGLT2 Inhibitor (Start First - Minimal BP Effect)

• Empagliflozin 10 mg once daily OR Dapagliflozin 10 mg once daily 1, 2
• No dose titration required—10 mg provides maximal benefit 2
• Can be used if eGFR ≥30 mL/min/1.73 m² (empagliflozin) or ≥20 mL/min/1.73 m² (dapagliflozin) 1
• Benefits occur within weeks of initiation 1

2. Mineralocorticoid Receptor Antagonist (Start Concurrently)

• Spironolactone 12.5-25 mg once daily OR Eplerenone 25 mg once daily 1, 2
• Requires potassium <5.0 mEq/L and eGFR >30 mL/min/1.73 m² before starting 1
• Eplerenone avoids gynecomastia (5.7% higher rate with spironolactone) 1

3. Beta-Blocker (Evidence-Based Only)

• Carvedilol 3.125 mg twice daily OR Metoprolol succinate 12.5-25 mg once daily OR Bisoprolol 1.25 mg once daily 1, 2
• Use carvedilol if refractory hypertension present (combined α1-β1-β2 blockade) 1
• Never use atenolol, propranolol, or other non-evidence-based beta-blockers 2

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan 49/51 mg twice daily (preferred for NYHA II-III) 1, 2, 4
• If switching from ACE inhibitor: mandatory 36-hour washout period to avoid angioedema 1, 4
• Alternative if ARNI not tolerated: Enalapril 2.5 mg twice daily OR Lisinopril 2.5-5 mg once daily 2
• Never combine ACE inhibitor with ARNI 1, 2

Loop Diuretics for Volume Management (Add Only If Congestion Present)

• Furosemide 20-40 mg once or twice daily OR Torsemide 10-20 mg once daily OR Bumetanide 0.5-1.0 mg once or twice daily 2
• Titrate to achieve euvolemia (no edema, no orthopnea, no JVD), then use lowest dose that maintains this state 1
• Loop diuretics control symptoms but do not reduce mortality 2

Critical Implementation Strategy

Why Simultaneous Initiation Matters:

• Combined quadruple therapy reduces mortality by approximately 73% over 2 years compared to no treatment 1
• Transitioning from dual therapy to quadruple therapy extends life expectancy by approximately 6 years 1
• Less than 25% of eligible patients currently receive all medications concurrently, and only 1% receive target doses—this represents a massive treatment gap 1
• Sequential initiation delays life-saving benefits 1, 2

Uptitration Protocol

Increase one drug at a time every 1-2 weeks until target doses achieved: 1, 2

1. SGLT2 inhibitor: Already at target dose (10 mg)—no titration needed 2
2. MRA: Spironolactone to 25-50 mg daily OR Eplerenone to 50 mg daily 1
3. Beta-blocker: Carvedilol to 25 mg twice daily, Metoprolol succinate to 200 mg daily, OR Bisoprolol to 10 mg daily 1, 2
4. ARNI: Sacubitril/valsartan to 97/103 mg twice daily after 2-4 weeks 1, 4

Monitoring at 1-2 weeks after each dose increment: 1, 2

• Blood pressure (target SBP >80 mmHg with adequate perfusion)
• Renal function (creatinine increases up to 30% above baseline are acceptable) 1
• Electrolytes (potassium, sodium)
• Volume status and symptoms

Managing Low Blood Pressure During Optimization

Never discontinue GDMT for asymptomatic hypotension with adequate perfusion—patients tolerate SBP 80-100 mmHg. 1, 2

If symptomatic hypotension (SBP <80 mmHg or major symptoms) occurs:

Step 1: Address Reversible Non-HF Causes First 1, 2

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin) 1
• Discontinue other non-essential BP-lowering medications 1
• Evaluate for dehydration, infection, acute illness 1

Step 2: Non-Pharmacological Interventions 1

• Compression leg stockings for orthostatic symptoms
• Exercise and physical training programs
• Space out medication timing throughout the day
• Adequate salt and fluid intake if not volume overloaded

Step 3: Modify GDMT Only If Steps 1-2 Fail 1

• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1
• If heart rate >70 bpm: reduce ARNI/ACE inhibitor/ARB dose first 1
• If heart rate <60 bpm: reduce beta-blocker dose first 1

Critical caveat: Discontinuing RAAS inhibitors after hypotension is associated with 2-4 fold higher risk of subsequent adverse events compared to continuing therapy 1

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 1
• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 1
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose 1

Self-Identified Black Patients with NYHA Class III-IV

• Add hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily to quadruple therapy 1, 2

Atrial Fibrillation

• Continue evidence-based beta-blockers (carvedilol, metoprolol succinate, bisoprolol) for rate control 2
• If beta-blocker not tolerated hemodynamically, consider ivabradine as alternative for heart rate control 1

Chronic Kidney Disease

• SGLT2 inhibitors are safe and effective with eGFR ≥30 mL/min/1.73 m² (empagliflozin) or ≥20 mL/min/1.73 m² (dapagliflozin) 1
• MRAs can be used if eGFR >30 mL/min/1.73 m² 1
• More frequent monitoring required in elderly patients and those with CKD 1

Medications to Absolutely Avoid in HFrEF

• Non-dihydropyridine calcium channel blockers (diltiazem, verapamil)—increase risk of worsening HF and hospitalization 1, 2
• Moxonidine—increases mortality 1
• Triple combination of ACE inhibitor + ARB + MRA—excessive hyperkalemia and renal dysfunction risk 1, 2
• Non-evidence-based beta-blockers (atenolol, propranolol)—no proven mortality benefit 2

Device Therapy Considerations (After 3 Months of Optimal Medical Therapy)

ICD for Primary Prevention: 2, 3

• LVEF ≤35%, NYHA Class II-III symptoms
• Expected survival >1 year with good functional status
• After ≥3 months of optimal medical therapy

Cardiac Resynchronization Therapy (CRT): 2, 3

• LVEF ≤35%, NYHA Class II-IV symptoms
• Sinus rhythm with QRS ≥150 msec and LBBB morphology

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—start simultaneously, not sequentially 1, 2
2. Accepting suboptimal doses—only 1% of patients receive target doses of all medications 1
3. Stopping medications for asymptomatic hypotension—patients with adequate perfusion tolerate SBP 80-100 mmHg 1
4. Overreacting to modest creatinine elevation—increases up to 30% above baseline are acceptable 1
5. Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol reduce mortality 1, 2
6. Inadequate monitoring—check BP, renal function, and electrolytes 1-2 weeks after each dose change 1, 2

Follow-Up Strategy

• Early follow-up within 7-14 days after medication adjustments 1, 3
• Refer to HF specialty care for newly diagnosed HFrEF to maximize GDMT optimization 1, 3
• Nurse-led titration programs reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92) 1
• Pharmacist involvement improves GDMT adherence and dosing 1, 3