Treatment Pillars for Heart Failure with Reduced Ejection Fraction
Four Foundational Medication Classes
All patients with symptomatic HFrEF (NYHA Class II-IV) should be started on four foundational medication classes simultaneously as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with loop diuretics for volume management. 1, 2 This quadruple therapy provides approximately 61% reduction in all-cause mortality (HR 0.39,95% CI: 0.32-0.49) and adds approximately 5.3 additional life-years compared to no treatment. 2
Pillar 1: SGLT2 Inhibitors (Start First)
- Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily should be initiated immediately, as these agents reduce cardiovascular death and heart failure hospitalization regardless of diabetes status with minimal blood pressure effect, making them ideal first agents. 1, 2
- No dose titration is required—the 10 mg dose provides maximal benefit without dose-response relationship. 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
Pillar 2: Mineralocorticoid Receptor Antagonists (Start First)
- Spironolactone 12.5-25 mg once daily (starting dose) should be initiated simultaneously with SGLT2 inhibitor, as it provides at least 20% mortality reduction and reduces sudden cardiac death with minimal blood pressure effect. 1, 2, 3
- Target dose: 50 mg once daily after 8 weeks if tolerated. 2
- Can be used if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L. 2
- If gynecomastia develops (occurs in ~10% of patients), switch to eplerenone. 2
Pillar 3: Beta-Blockers (Start 1-2 Weeks Later)
- Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol—these reduce mortality by at least 20% and decrease sudden cardiac death. 1, 2
- Starting doses:
- Carvedilol: 3.125 mg twice daily
- Metoprolol succinate: 12.5-25 mg once daily
- Bisoprolol: 1.25 mg once daily 1
- Target doses:
- Titrate every 2 weeks if heart rate remains ≥70 bpm. 1
Pillar 4: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) (Start 1-2 Weeks After Beta-Blocker)
- Sacubitril/valsartan (Entresto) is preferred over ACE inhibitors as it provides superior mortality reduction of at least 20% compared to ACE inhibitors. 2, 4
- Starting dose: 49/51 mg twice daily (or 24/26 mg twice daily if not previously on ACE inhibitor/ARB, severe renal impairment, or moderate hepatic impairment). 1, 4
- Target dose: 97/103 mg twice daily after 2-4 weeks. 1, 4
- Critical safety requirement: Allow 36-hour washout period after stopping ACE inhibitor before starting sacubitril/valsartan to avoid angioedema. 2, 4
- Requires systolic BP >100 mmHg, eGFR >30 mL/min/1.73 m², and potassium <5.2 mmol/L. 2
Alternative if ARNI not tolerated: ACE inhibitor (e.g., enalapril 2.5-5 mg twice daily, target 10-20 mg twice daily) or ARB (e.g., losartan 25-50 mg once daily, target 150 mg once daily). 1, 2
Pillar 5: Loop Diuretics (For Symptom Control Only)
- Furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily for congestion control. 1
- Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state. 2
- Critical caveat: Diuretics do not reduce mortality—they are for symptom management only. 1
Rapid Sequencing Strategy (Complete Within 2-4 Weeks)
Week 1: Start SGLT2 inhibitor + MRA simultaneously (minimal BP effects allow safe initiation). 1, 5
Week 2-3: Add low-dose beta-blocker if heart rate >70 bpm. 1, 5
Week 3-4: Add low-dose sacubitril/valsartan (after 36-hour ACE inhibitor washout if applicable). 1, 5
Weeks 4-12: Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose achieved. 1, 2
Priority order for titration: SGLT2 inhibitor and MRA first (already at target doses), then beta-blocker, then ARNI. 1
Typical Target Doses Summary
| Drug Class | Starting Dose | Target Dose | Frequency |
|---|---|---|---|
| Dapagliflozin | 10 mg | 10 mg | Once daily |
| Empagliflozin | 10 mg | 10 mg | Once daily |
| Spironolactone | 12.5-25 mg | 50 mg | Once daily |
| Carvedilol | 3.125 mg | 25 mg (50 mg if >85 kg) | Twice daily |
| Metoprolol succinate | 12.5-25 mg | 200 mg | Once daily |
| Bisoprolol | 1.25 mg | 10 mg | Once daily |
| Sacubitril/valsartan | 49/51 mg | 97/103 mg | Twice daily |
| Furosemide | 20-40 mg | Titrate to euvolemia | Once or twice daily |
Additional Therapies for Selected Patients
Ivabradine (If Heart Rate ≥70 bpm Despite Maximally Tolerated Beta-Blocker)
- Indication: Symptomatic HFrEF patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker dose. 2, 6
- Starting dose: 2.5-5 mg twice daily with food. 1, 6
- Target dose: 7.5 mg twice daily after 2 weeks based on heart rate. 6
- Contraindications: Acute decompensated HF, clinically significant hypotension or bradycardia, sick sinus syndrome, 2nd or 3rd degree AV block without pacemaker, severe hepatic impairment. 6
Hydralazine/Isosorbide Dinitrate (For Self-Identified Black Patients)
- Indication: Self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 1
- Starting dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily. 1
- Target dose: Hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily. 1
Critical Contraindications to Avoid
- Never combine ACE inhibitor with ARNI—risk of angioedema. 2, 4
- Never use triple combination of ACE inhibitor + ARB + MRA—extreme hyperkalemia and renal dysfunction risk. 1, 2
- Avoid diltiazem or verapamil in HFrEF—they worsen heart failure and increase hospitalization risk (Class III, Harm). 1, 2
- Avoid non-evidence-based beta-blockers (e.g., atenolol, labetalol)—no proven mortality benefit. 1
Managing Low Blood Pressure During Optimization
- Never discontinue or down-titrate GDMT for asymptomatic hypotension with adequate perfusion—GDMT maintains efficacy and safety even with baseline SBP <110 mmHg. 1, 2
- For symptomatic hypotension (SBP <80 mmHg or major symptoms):
- First: Stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration/infection. 2
- Second: Use non-pharmacological interventions (compression leg stockings, exercise programs, adequate salt/fluid intake if not volume overloaded). 2
- Third: If symptoms persist, reduce GDMT in this order: If heart rate >70 bpm, reduce ARNI dose first; if heart rate <60 bpm, reduce beta-blocker dose first. Always maintain SGLT2 inhibitor and MRA (minimal BP effects). 2
Monitoring Requirements
- Check blood pressure, renal function, and electrolytes:
- Acceptable changes during titration:
Device Therapy Timing
Implantable Cardioverter-Defibrillator (ICD)
- Indication: LVEF ≤35% despite ≥3 months of optimal medical therapy, NYHA Class II-III, expected survival >1 year with good functional status. 1, 2
- Do not implant within 40 days of myocardial infarction—no prognostic benefit during this period (Class III, Level A). 1
Cardiac Resynchronization Therapy (CRT)
- Indication: Sinus rhythm with QRS ≥150 msec, LBBB morphology, LVEF ≤35% despite optimal medical therapy (Class I, Level A). 1, 2
Common Pitfalls to Avoid
- Delaying initiation of all four medication classes—start simultaneously within 2-4 weeks. 1, 5
- Accepting suboptimal doses—low starting doses have substantial benefit, but target doses provide maximal mortality reduction. 1, 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. 2
- Inadequate monitoring—check renal function and electrolytes 1-2 weeks after each dose adjustment. 2
- Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol have proven mortality benefit. 1, 2