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

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with symptomatic HFrEF should immediately start quadruple therapy—consisting of an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated)—simultaneously at low doses as soon as the diagnosis is confirmed, along with loop diuretics for volume management. 1, 2

Diagnostic Confirmation

Before initiating therapy, confirm the diagnosis with:

• Transthoracic echocardiography documenting LVEF ≤40% 2
• Baseline blood pressure, heart rate, renal function (eGFR), and serum potassium 2
• Volume status assessment (peripheral edema, jugular venous distension, pulmonary rales) 3

Foundational Quadruple Therapy: Simultaneous Initiation

Start all four medication classes simultaneously at low doses within the first 4-6 weeks of diagnosis—this approach reduces mortality risk by approximately 73% over 2 years compared to no treatment. 1, 2

1. SGLT2 Inhibitors (Start First)

• Empagliflozin 10 mg once daily OR Dapagliflozin 10 mg once daily 1, 3
• No dose titration required—10 mg provides maximal benefit 3
• Benefits occur within weeks of initiation 1, 3
• Minimal blood pressure effect, making them ideal first agents 1, 2
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 1, 3
• Reduces cardiovascular death and HF hospitalization regardless of diabetes status 1, 3, 2

2. Mineralocorticoid Receptor Antagonists (Start Simultaneously)

• Spironolactone 12.5-25 mg once daily OR Eplerenone 25 mg once daily 1, 3
• Target dose: Spironolactone 25-50 mg daily OR Eplerenone 50 mg daily 1
• Provides at least 20% reduction in mortality risk and reduces sudden cardiac death 1, 3, 2
• Can be used if eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L 1, 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 1

3. Beta-Blockers

Use only evidence-based beta-blockers:

• Carvedilol: Start 3.125 mg twice daily, target 25 mg twice daily (50 mg twice daily if >85 kg) 3, 2
• Metoprolol succinate: Start 12.5-25 mg once daily, target 200 mg once daily 3, 2, 4
• Bisoprolol: Start 1.25 mg once daily, target 10 mg once daily 3, 2

Provides at least 20% reduction in mortality and decreases sudden cardiac death 1, 3, 2

For NYHA Class II heart failure, start metoprolol succinate at 25 mg once daily; for more severe heart failure (Class III-IV), start at 12.5 mg once daily. 4

Carvedilol is preferred if refractory hypertension is present due to its combined α1-β1-β2-blocking properties. 1

4. ARNI (Preferred) or ACE Inhibitor/ARB

ARNI (Sacubitril/Valsartan) is preferred over ACE inhibitors:

• Start 24/26 mg or 49/51 mg twice daily, target 97/103 mg twice daily 1, 3
• Provides at least 20% additional mortality reduction compared to ACE inhibitors 1, 3, 2
• When switching from ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 1
• ARNI actually reduces hyperkalemia risk when combined with MRAs compared to ACE inhibitors plus MRAs 3

If ARNI not tolerated or available:

• ACE inhibitors (enalapril, lisinopril, ramipril) reduce mortality by 5-16% 1
• ARBs (losartan, valsartan, candesartan) are alternatives if ACE inhibitors cause intolerable cough 5, 1

Loop Diuretics for Volume Management

Loop diuretics are essential for congestion control but do not reduce mortality:

• Furosemide 20-40 mg once or twice daily 3
• Torsemide 10-20 mg once daily 3
• Bumetanide 0.5-1.0 mg once or twice daily 3

Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 3

For hospitalized patients, initial IV dose should equal or exceed chronic oral daily dose, titrating based on urine output and congestion symptoms. 1

Uptitration Strategy

Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved:

1. Prioritize SGLT2 inhibitor and MRA first (minimal BP effects) 1, 3
2. Then uptitrate beta-blocker 1, 3
3. Then uptitrate ARNI/ACE inhibitor/ARB 1, 3

Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, with more frequent monitoring in elderly patients and those with chronic kidney disease. 1, 3

Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 1, 3

Managing Low Blood Pressure During Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 1, 3

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

1. Address reversible non-HF causes first: Stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration/infection 1, 3
2. Non-pharmacological interventions: Compression leg stockings for orthostatic symptoms, exercise programs, adequate salt/fluid intake if not volume overloaded 1, 3
3. If symptoms persist, reduce GDMT in this specific order:
   • If heart rate >70 bpm: Reduce ACEi/ARB/ARNI dose first 3
   • If heart rate <60 bpm: Reduce beta-blocker dose first 3
   • Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 3

Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 3

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with NYHA Class III-IV Symptoms

Add hydralazine/isosorbide dinitrate to quadruple therapy:

• Hydralazine 25 mg three times daily + Isosorbide dinitrate 20 mg three times daily 3
• Target: Hydralazine 75 mg three times daily + Isosorbide dinitrate 40 mg three times daily 1, 3

For Persistent Symptoms Despite Optimal Therapy

Ivabradine is considered if:

• Heart rate ≥70 bpm in sinus rhythm 3, 2
• On maximally tolerated beta-blocker 3, 2
• Start 2.5-5 mg twice daily 3

Vericiguat may be considered for patients with worsening heart failure despite optimal therapy. 6

Device Therapy

Implantable Cardioverter-Defibrillator (ICD)

Indicated for primary prevention in patients with:

• LVEF ≤35% 3, 2
• NYHA class II-III symptoms 3, 2
• Expected survival >1 year with good functional status 3, 2
• ≥3 months of optimal medical therapy 3

Cardiac Resynchronization Therapy (CRT)

Indicated for patients with:

• LVEF ≤35% 3, 2
• NYHA class II-IV symptoms 3, 2
• Sinus rhythm 3, 2
• QRS ≥150 msec with left bundle branch block (LBBB) morphology 3, 2

Critical Contraindications and Medications to Avoid

Never combine:

• ACE inhibitor with ARNI (risk of angioedema) 1, 3
• Triple combination of ACE inhibitor + ARB + MRA (risk of hyperkalemia and renal dysfunction) 1, 3

Avoid in HFrEF:

• Non-dihydropyridine calcium channel blockers (diltiazem, verapamil)—increase risk of worsening heart failure and hospitalization 1, 3
• Alpha-blockers (tamsulosin, doxazosin)—interfere with GDMT optimization 1
• Moxonidine—may increase mortality 1

Monitoring Requirements

At 1-2 weeks after each dose increment:

• Blood pressure 1, 3
• Renal function (creatinine, eGFR) 1, 3
• Electrolytes (potassium) 1, 3
• Symptoms of worsening heart failure 1

If hyperkalemia develops (K+ >5.5 mEq/L), consider potassium binders like patiromer rather than discontinuing life-saving medications. 3

Implementation Strategies

Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization. 1, 2

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, 2

Early follow-up within 7-14 days after medication adjustments is recommended. 1, 2

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses 1
• Accepting suboptimal doses—target doses provide the greatest mortality benefit 1
• Stopping medications for asymptomatic hypotension—patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 3
• Overreacting to modest creatinine elevation—up to 30% above baseline is acceptable 1, 3
• Using non-evidence-based beta-blockers (atenolol, propranolol)—only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit 1, 3

Quality of Life Considerations

High certainty evidence demonstrates improved HRQoL with:

• SGLT2 inhibitors (SMD 0.16,95% CI 0.08–0.23) 5
• ARBs (SMD 0.09,95% CI 0.02–0.17) 5
• ARNI compared with ACE inhibitor (SMD 0.09,95% CI 0.02–0.17) 5
• Ivabradine (SMD 0.14,95% CI 0.04–0.23) 5
• Hydralazine-nitrate (SMD 0.24,95% CI 0.04–0.44) 5
• Intravenous iron (SMD 0.52,95% CI 0.04–1.00) 5

Intravenous iron replacement is recommended in patients with iron deficiency to improve functional status and quality of life. 6

Expected Outcomes

Combined quadruple therapy reduces all-cause mortality by 61% (HR 0.39,95% CI: 0.32-0.49). 3

Transitioning from traditional dual therapy (ACEi and beta-blocker) to quadruple therapy can extend life expectancy by approximately 6 years. 1