What is the guideline‑directed medical regimen for a patient with heart failure with reduced ejection fraction (left ventricular ejection fraction ≤40%)?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction (LVEF ≤40%)

All patients with HFrEF should immediately receive four foundational medication classes simultaneously: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), an evidence-based beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with loop diuretics for volume management. 1, 2

The Four Pillars of HFrEF Therapy

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily 1, 2
• Reduce cardiovascular death and HF hospitalization by approximately 25% regardless of diabetes status 1, 2
• No dose titration required—maximal benefit at starting dose 2
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making them ideal first agents 2
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 2
• Benefits occur within weeks of initiation 2

2. Mineralocorticoid Receptor Antagonists (Start Simultaneously with SGLT2i)

• Spironolactone 12.5-25 mg once daily, titrate to 50 mg daily over 4-8 weeks 1, 2
• Alternative: Eplerenone 25 mg once daily, titrate to 50 mg daily 1, 2
• Provide at least 20% mortality reduction and reduce sudden cardiac death 1, 2
• Minimal blood pressure effect allows early initiation 2
• Requires eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L before starting 2
• Switch to eplerenone if gynecomastia develops (occurs in ~10% with spironolactone) 2

3. Evidence-Based Beta-Blockers

Only three beta-blockers have proven mortality benefit in HFrEF: 1, 2

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

Critical: Metoprolol tartrate (immediate-release) has never shown mortality benefit and should not be used 2

Beta-blockers reduce mortality by 34%—the highest relative risk reduction among the four medication classes 2

4. Renin-Angiotensin System Inhibitors

For symptomatic patients (NYHA class II-IV):

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors 1, 2
• Start 49/51 mg twice daily, titrate to 97/103 mg twice daily over 3-5 weeks 2
• Provides at least 20% mortality reduction superior to ACE inhibitors 1, 2
• Requires 36-hour washout period after stopping ACE inhibitor to avoid angioedema 2

For asymptomatic patients (NYHA class I) or if ARNI not tolerated:

• ACE inhibitors: Enalapril 2.5-5 mg twice daily, target 10 mg twice daily; or Lisinopril 2.5-5 mg once daily, target 20-40 mg once daily 1, 2
• ARBs (if ACE inhibitor not tolerated): Losartan 25-50 mg once daily, target 150 mg once daily; or Valsartan 40 mg twice daily, target 160 mg twice daily 1, 2

Diuretics for Volume Management

Loop diuretics are essential for congestion control but do not reduce mortality: 2

• Furosemide 20-40 mg once or twice daily 2
• Torsemide 10-20 mg once daily 2
• Bumetanide 0.5-1.0 mg once or twice daily 2

Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state 2

Titration Strategy: The Sequential Approach

Start SGLT2 inhibitor and MRA first (minimal BP effects), then add beta-blocker, then ARNI 1, 2

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

Specific Titration Sequence:

1. Week 0: Start SGLT2i (full dose) + MRA (12.5-25 mg) + diuretic as needed 2
2. Week 2: Increase MRA to 50 mg if tolerated 2
3. Week 4: Start beta-blocker at low dose 2
4. Week 6: Increase beta-blocker dose 2
5. Week 8: Continue beta-blocker titration every 2 weeks until target dose 2
6. Week 12-16: Start ARNI (if symptomatic) or continue ACE inhibitor 2
7. Week 18-22: Titrate ARNI to target dose 2

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 2

For Symptomatic Hypotension (SBP <80 mmHg or Major Symptoms):

Step 1: Address reversible non-HF causes first 2

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 2
• Discontinue other non-essential BP-lowering medications 2
• Evaluate for dehydration, infection, or acute illness 2

Step 2: Non-pharmacological interventions 2

• Compression leg stockings for orthostatic symptoms 2
• Exercise and physical training programs 2
• Adequate salt and fluid intake if not volume overloaded 2
• Space out medication administration throughout the day 2

Step 3: If symptoms persist, reduce GDMT in this specific order 2

• If heart rate >70 bpm: Reduce ACEi/ARB/ARNI dose first 2
• If heart rate <60 bpm: Reduce beta-blocker dose first 2
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 2

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1, 2
• Start hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• Titrate to hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 2

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1, 2
• Start 2.5-5 mg twice daily, target 7.5 mg twice daily 2
• Survival benefit is modest or negligible in the broad HFrEF population 2

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for primary prevention in patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, who are expected to survive >1 year with good functional status 1, 2

Cardiac Resynchronization Therapy (CRT)

• Recommended for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and left bundle branch block (LBBB) morphology with LVEF ≤35% despite optimal medical therapy 1, 2

Critical Contraindications and Medications to Avoid

Never combine ACE inhibitor with ARNI—risk of angioedema 2

Never use triple combination of ACE inhibitor + ARB + MRA—extreme hyperkalemia and renal dysfunction risk 1, 2

Avoid diltiazem or verapamil in HFrEF—they increase risk of worsening heart failure and hospitalization 2

Avoid non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate)—no proven mortality benefit 2

Avoid NSAIDs and COX-2 inhibitors—worsen fluid retention and renal function 1

Monitoring Requirements

At 1-2 weeks after each dose increment: 2

• Blood pressure 2
• Heart rate 2
• Serum creatinine and eGFR 2
• Serum potassium 2

More frequent monitoring required for: 2

• Elderly patients 2
• Chronic kidney disease 2
• Baseline potassium >4.5 mEq/L 2

Acceptable changes during titration: 2

• Creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation 2
• Potassium up to 5.5 mEq/L can be managed with potassium binders (patiromer) rather than stopping MRA 2

Common Pitfalls to Avoid

Delaying initiation of all four medication classes—start simultaneously as soon as possible after diagnosis 1, 2

Accepting suboptimal doses—clinical trials demonstrated benefits at target doses, not low doses 2

Stopping medications for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms 2

Inadequate monitoring—leads to preventable adverse events and unnecessary discontinuation 2

Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, and bisoprolol reduce mortality 2

Discontinuing RAASi after hyperkalemia—associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy with potassium binders 2

Expected Outcomes with Optimal Therapy

When all four medication classes are used at target doses, patients experience: 2

• 61% reduction in all-cause mortality (HR 0.39,95% CI 0.32-0.49) 2
• Approximately 5.3 additional life-years compared to no treatment 2
• Significant reduction in heart failure hospitalizations 1, 2
• Improved quality of life and functional capacity 1, 2

Referral Criteria

Refer to heart failure specialist when: 1, 2

• Patient remains symptomatic despite optimal GDMT 1
• Considering mechanical circulatory support or transplantation evaluation 2
• Difficulty achieving target doses due to adverse effects 2
• Advanced heart failure (NYHA class IV, recurrent hospitalizations) 1