How should I initiate treatment for an adult with symptomatic reduced‑ejection‑fraction heart failure?

Initiating Treatment for Symptomatic Heart Failure with Reduced Ejection Fraction

Start all 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 if ARNI unavailable), which together provide approximately 73% mortality reduction over 2 years. 1

Foundational Quadruple Therapy (Start Immediately)

The contemporary approach prioritizes rapid initiation of comprehensive guideline-directed medical therapy (GDMT) rather than sequential uptitration, as early benefit occurs with prompt initiation. 1

1. SGLT2 Inhibitor (e.g., Dapagliflozin 10 mg daily)

• Initiate first as it has minimal blood pressure effect and reduces cardiovascular death and heart failure hospitalization regardless of diabetes status 1
• Can be started even with eGFR as low as 25 mL/min/1.73 m² 2
• No dose adjustment needed based on age or hepatic impairment 2

2. Mineralocorticoid Receptor Antagonist (Spironolactone or Eplerenone)

• Provides at least 20% mortality reduction and reduces sudden cardiac death 1
• Has minimal blood pressure effect, allowing early initiation 1
• Particularly recommended for NYHA class III-IV patients 3
• Critical monitoring: Check potassium and creatinine after 5-7 days, then every 5-7 days until stable 3

3. Beta-Blocker (Bisoprolol, Metoprolol Succinate, Carvedilol, or Nebivolol)

• Reduces mortality by at least 20% and decreases sudden cardiac death 1
• Start low: Carvedilol 3.125 mg twice daily 1
• Titrate up every 1-2 weeks as tolerated 1
• Recommended for all stable patients NYHA class II-IV 3, 4
• If patient already on a beta-blocker for another condition, switch to one of these four evidence-based agents 3

4. ARNI (Sacubitril/Valsartan) - Preferred Over ACE Inhibitors

• ARNI is superior: Provides at least 20% greater mortality reduction compared to ACE inhibitors 1
• Starting dose: 24 mg/26 mg twice daily (or 49 mg/51 mg twice daily if tolerated) 1
• For severe renal impairment (eGFR <30 mL/min), start at 24 mg/26 mg twice daily 1
• If ARNI unavailable or contraindicated: Use ACE inhibitor as alternative 3, 4
• Never combine ACE inhibitor with ARNI; allow 36-hour washout period when switching 1

Diuretic Therapy (Add as Needed for Congestion)

• Essential for symptomatic relief when fluid overload is present 4
• Always administer with ACE inhibitor/ARNI, never as monotherapy 3
• Loop diuretics preferred; if GFR <30 mL/min, do not use thiazides except synergistically with loop diuretics 3
• For insufficient response: increase dose, combine loop diuretics with thiazides, or administer loop diuretics twice daily 3

Critical Initiation Steps for ACE Inhibitor/ARNI

When initiating renin-angiotensin system blockade: 3

1. Review and optimize diuretic dosing first
2. Avoid excessive diuresis; consider withholding diuretics for 24 hours before starting
3. Start with low dose and build up to target doses proven effective in trials
4. Avoid potassium-sparing diuretics during initial therapy (until stable on MRA)
5. Avoid NSAIDs completely
6. Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment, at 3 months, then every 6 months 3

Monitoring Protocol

Initial Phase (First 3 Months)

• Blood pressure, heart rate, and clinical status after each dose titration 3, 1
• Renal function and electrolytes: 5-7 days after MRA initiation, then every 5-7 days until stable 3
• Renal function and electrolytes: 1-2 weeks after each ARNI/ACE inhibitor dose change 3

Maintenance Phase

• Every 6 months: blood pressure, renal function, electrolytes 3
• Consider specialist monitoring of natriuretic peptide levels in patients with problematic uptitration or history of hospitalization 3

Common Pitfalls to Avoid

• Do not delay initiation waiting for "stability" - start all four medications as soon as diagnosis confirmed 1
• Do not use sequential uptitration approach - simultaneous initiation provides superior outcomes 1
• Do not switch to ARB unless ACE inhibitor/ARNI side effects are truly intolerable; ACE inhibitors have stronger evidence base 3
• Avoid triple combination of ACE inhibitor + ARB + MRA due to severe hyperkalemia and renal dysfunction risk 4
• Do not use diltiazem or verapamil in HFrEF as they worsen heart failure 4
• Do not stop GDMT for asymptomatic low blood pressure - treatment weakens the association between low BP and poor prognosis 3

When to Stop or Adjust

• Stop ACE inhibitor/ARNI if renal function deteriorates substantially 3
• For symptomatic hypotension (SBP <80 mmHg): address reversible causes, stop non-HF medications first, but continue HF GDMT 3
• If severe hyperkalemia or renal dysfunction develops with MRA: reduce dose or temporarily hold, but attempt to restart at lower dose when stable 3

Additional Considerations

Patient Education

• Daily self-weighing to detect fluid retention early 1, 4
• Report weight gain >2 kg in 3 days 4
• Sodium restriction, fluid restriction in severe HF, alcohol limitation 3, 4
• Smoking cessation and regular physical activity 4

Device Therapy Evaluation

• ICD: Consider for LVEF ≤35% after ≥3 months optimal medical therapy in NYHA class II-III 1, 4
• CRT: Consider for QRS ≥150 msec with LBBB morphology, LVEF ≤35%, sinus rhythm, despite optimal medical therapy 1, 4