How to manage heart failure with reduced ejection fraction (HFrEF)?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should receive four foundational medication classes simultaneously: an ARNI (or ACEi/ARB if ARNI not feasible), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, initiated as early as possible even at low doses, with rapid up-titration to target doses within 2 months. 1

Core Pharmacological Therapy - The Four Pillars

1. Renin-Angiotensin System Inhibition (First Priority)

• ARNI (sacubitril/valsartan) is the preferred first-line agent for patients with NYHA class II-III symptoms to reduce morbidity and mortality 1
• If already on ACEi or ARB and tolerating it, replace with ARNI to further reduce morbidity and mortality 1
• ACEi (e.g., lisinopril) is recommended when ARNI is not feasible, proven to reduce mortality in HFrEF 1, 2
• ARB is recommended only if ACEi causes cough or angioedema and ARNI is not feasible 1

2. Beta-Blockers (Equal Priority)

• Evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) are mandatory for all HFrEF patients unless contraindicated 1
• Target heart rate <70 bpm; if not achieved with beta-blocker alone, add ivabradine for patients in sinus rhythm 1
• In patients with low blood pressure, consider switching carvedilol to metoprolol or bisoprolol as they may have less hypotensive effect 1

3. Mineralocorticoid Receptor Antagonists

• Spironolactone is indicated for NYHA class III-IV HFrEF with ejection fraction ≤35% to increase survival, manage edema, and reduce hospitalization 3
• The landmark RALES trial showed 30% reduction in mortality risk with spironolactone in severe HFrEF 3
• Monitor potassium and creatinine closely; exclude if baseline K+ >5.0 mEq/L or creatinine >2.5 mg/dL 3

4. SGLT2 Inhibitors (Newest Pillar)

• SGLT2 inhibitors (dapagliflozin or empagliflozin) are now Class 1 recommendations for all HFrEF patients regardless of diabetes status 1
• Major advantage: once-daily dosing without up-titration needed, minimal blood pressure effects, and early onset of benefits 1
• Can be initiated in patients with eGFR >20 mL/min/1.73m² 1

Practical Implementation Algorithm

Initial Therapy Approach

Start all four medication classes simultaneously at low doses rather than sequentially achieving target doses of fewer medications 1, 4. This approach is superior because:

• Earlier establishment of comprehensive disease-modifying therapy 4
• Faster achievement of optimal treatment (within 2 months in most patients) 4
• Improved mortality and morbidity outcomes even at lower doses of all four classes versus high doses of fewer classes 1

Up-Titration Strategy

• Increase doses every 1-2 weeks as tolerated, targeting evidence-based doses 4
• Do not wait to achieve target dose of one medication before starting the next 1
• Sequence of up-titration can be guided by clinical factors (heart rate, blood pressure, renal function, potassium) 1

Monitoring Parameters During Titration

• Every 1-2 weeks initially: blood pressure, heart rate, symptoms, weight 4
• Every 2-4 weeks: serum potassium, creatinine, eGFR 3, 4
• Adjust based on safety thresholds: SBP <90 mmHg, HR <50 bpm, K+ >5.5 mEq/L, significant worsening of renal function 1

Managing Low Blood Pressure During Optimization

This is a critical challenge that often limits GDMT implementation. Low blood pressure alone (even <90 mmHg) without symptoms or hypoperfusion is NOT a contraindication to GDMT 1.

Differentiate Clinical Scenarios

If low BP with normal perfusion (asymptomatic):

• Continue all four GDMT classes 1
• Space out medication timing throughout the day to reduce synergistic hypotensive effects 1
• Implement non-pharmacological interventions: exercise training, compression stockings 1

If low BP with symptomatic hypotension or hypoperfusion:

• First, stop all non-GDMT medications that lower blood pressure (other antihypertensives, nitrates, alpha-blockers) 1
• Prioritize continuing SGLT2 inhibitors and MRAs as they have minimal BP effects 1

Sequenced Down-Titration Algorithm (Only if Severely Symptomatic)

When symptomatic hypotension persists despite stopping non-GDMT drugs, follow this hierarchy 1:

If eGFR <30 mL/min/1.73m²:

1. Reduce ARNI/ACEi/ARB first
2. Then reduce MRA if needed

If K+ >5.0 mEq/L:

1. Reduce MRA first
2. Then reduce beta-blocker if needed

If HR <60 bpm:

1. Stop ivabradine if on it
2. Reduce ARNI/ACEi/ARB
3. Consider cardiac pacing (CRT) if indicated

If HR >70 bpm:

1. Reduce ARNI/ACEi/ARB first

If no specific clinical profile:

1. Reduce ARNI/ACEi/ARB first

Critical caveat: Discontinuing GDMT due to side effects is associated with worse outcomes than the side effects themselves 1. Every effort should be made to maintain therapy.

Acute Decompensated HFrEF Management

Immediate Priorities

• Start IV loop diuretics immediately in the emergency department without delay—do not wait for hospital admission 5
• Initial IV dose should equal or exceed chronic oral daily dose 5
• Add non-invasive ventilation for respiratory distress 5
• Never give IV fluids to patients with volume overload (orthopnea, dyspnea, edema) 5

GDMT During Hospitalization

• Continue chronic ACEi/ARB/ARNI and beta-blockers unless hemodynamic instability or cardiogenic shock present 5, 6
• Continue SGLT2 inhibitors and MRAs during hospitalization as they provide ongoing benefit with minimal hemodynamic effects 6
• Monitor for worsening renal function, hypokalemia, hypomagnesemia 5

Post-Discharge Optimization

• Initiate or optimize all four GDMT classes before discharge or within days of discharge 1
• Patients with lower baseline blood pressure may require more gradual up-titration and closer post-discharge monitoring 1
• Close follow-up within 1-2 weeks of discharge is essential 1

Device Therapy Considerations

• ICD for primary prevention if LVEF ≤35% despite ≥3 months of optimal GDMT and life expectancy >1 year 1
• CRT for patients with LVEF ≤35%, NYHA class II-IV, sinus rhythm, and LBBB with QRS ≥150 ms 1
• Device decisions should be made after achieving optimal medical therapy 1

Advanced HF Referral Criteria

Refer to HF specialty team if: 1

• Persistent NYHA class III-IV symptoms despite optimal GDMT
• Recurrent hospitalizations for HF
• Need for continuous or intermittent inotropic support
• Consideration for advanced therapies (transplant, mechanical circulatory support)

Common Pitfalls to Avoid

• Never delay starting all four medication classes waiting to reach target dose of one medication 1, 4
• Never withhold GDMT solely based on asymptomatic low blood pressure (<90 mmHg) without evidence of hypoperfusion 1
• Never discontinue GDMT during sepsis or acute illness unless true hemodynamic instability exists 6
• Never use ARB as first-line therapy—ARNI or ACEi are superior 1
• Never forget to monitor potassium and renal function every 1-2 weeks during initiation and up-titration 3, 4
• Never assume older or frail patients cannot tolerate GDMT—they benefit equally but may need slower titration 1, 4