What is the guideline‑directed medical management for a patient with heart failure with reduced ejection fraction (approximately 20%)?

Management of Heart Failure with Reduced Ejection Fraction (EF 20%)

You must immediately initiate all four foundational medication classes simultaneously at low doses and uptitrate every 1–2 weeks to target doses, as this quadruple therapy reduces 2-year mortality by approximately 73% compared to no treatment and adds 5.3 life-years per patient. 1

Immediate Medication Initiation (Start All Four Classes Now)

1. SGLT2 Inhibitor (Start First – No BP Effect)

• Dapagliflozin 10 mg once daily OR Empagliflozin 10 mg once daily 1, 2
• No dose titration required; full benefit at starting dose 1
• Minimal blood pressure effect (only 1.5 mmHg reduction, diminishing to <1 mmHg after 4 months) 1
• Benefits occur within weeks of initiation 1
• Safe if eGFR ≥20 mL/min/1.73 m² for dapagliflozin or ≥30 mL/min/1.73 m² for empagliflozin 1

2. Mineralocorticoid Receptor Antagonist (Start Simultaneously)

• Spironolactone 12.5–25 mg once daily OR Eplerenone 25 mg once daily 1, 3
• Uptitrate to spironolactone 50 mg daily or eplerenone 50 mg daily at 4–8 weeks if tolerated 1, 3
• Provides ≥20% mortality reduction 1, 3
• Minimal blood pressure effect 1
• Requires eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L 1
• Monitor potassium and creatinine at 1–2 weeks after each dose change 1

3. Beta-Blocker (Evidence-Based Only)

Choose ONE of these three:

• Carvedilol: start 3.125 mg twice daily → target 25–50 mg twice daily 1, 3
• Metoprolol succinate (NOT tartrate): start 12.5–25 mg once daily → target 200 mg once daily 1, 3
• Bisoprolol: start 1.25 mg once daily → target 10 mg once daily 1, 3

Critical: Only these three beta-blockers reduce mortality by ≥20% and lower sudden cardiac death risk 1, 3. Metoprolol tartrate has never shown mortality benefit and must not be used 3.

4. ARNI (Preferred) or ACE-Inhibitor/ARB

First-line choice:

• Sacubitril/valsartan (Entresto): start 24/26 mg or 49/51 mg twice daily → target 97/103 mg twice daily 1, 3, 4
• Provides ≥20% mortality reduction, superior to ACE-inhibitors 1, 3
• Requires 36-hour washout if switching from ACE-inhibitor (to avoid angioedema) 1
• Requires SBP >100 mmHg, eGFR >30 mL/min/1.73 m², potassium <5.2 mmol/L 3

If ARNI not tolerated:

• Lisinopril 10 mg daily → target 40 mg daily, OR
• Enalapril 2.5–5 mg twice daily → target 10–20 mg twice daily 1

Loop Diuretics for Volume Management (Not Mortality-Reducing)

• Furosemide 20–40 mg once or twice daily, OR
• Torsemide 10–20 mg once daily, OR
• Bumetanide 0.5–1.0 mg once or twice daily 3
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 3

Uptitration Protocol (Every 1–2 Weeks)

Week 0: Start all four classes at low doses simultaneously 1

Weeks 2,4,6,8: Increase one drug at a time using small increments 1:

1. First uptitrate SGLT2i and MRA (already at target or near-target doses)
2. Then uptitrate beta-blocker if heart rate >70 bpm
3. Then uptitrate ARNI/ACE-inhibitor/ARB 1

Monitor at 1–2 weeks after each dose change:

• Blood pressure, heart rate 1
• Renal function (creatinine, eGFR) 1
• Electrolytes (potassium, sodium) 1
• Volume status (weight, edema, orthopnea) 3

Managing Low Blood Pressure During Optimization

Never discontinue GDMT for asymptomatic hypotension if perfusion is adequate (SBP 80–100 mmHg is tolerable). 1

If SBP <80 mmHg or symptomatic hypotension:

1. First: Stop non-essential BP-lowering drugs (alpha-blockers for BPH, unnecessary antihypertensives) 1
2. Second: Evaluate for reversible causes (dehydration, infection, acute illness) 1
3. Third: Consider non-pharmacologic interventions (compression stockings, adequate salt/fluid intake if not volume-overloaded) 1
4. Only if steps 1–3 fail: Reduce GDMT in this order:
   • If heart rate >70 bpm: reduce ARNI/ACE-inhibitor/ARB dose first 1
   • If heart rate <60 bpm: reduce beta-blocker dose first 1
   • Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1

Device Therapy Considerations (After 3 Months of Optimal GDMT)

ICD for primary prevention:

• Indicated if LVEF remains ≤35% after ≥3 months of optimal GDMT, NYHA class II–III symptoms, and expected survival >1 year with good functional status 5, 3

Cardiac resynchronization therapy (CRT):

• Indicated if LVEF ≤35%, NYHA class II–IV, QRS ≥150 msec with left bundle branch block morphology, and sinus rhythm 5, 3

Advanced Heart Failure Referral Criteria

Refer to HF specialist if:

• Persistent NYHA class III–IV symptoms despite optimal GDMT 5
• LVEF <25% with high predicted 1–2-year mortality 5
• Dependence on continuous parenteral inotropic support 5
• Consideration for mechanical circulatory support or cardiac transplantation 5

Critical Contraindications to Avoid

• Never combine ACE-inhibitor with ARNI (angioedema risk) 1, 3
• Never use triple combination of ACE-inhibitor + ARB + MRA (hyperkalemia and renal dysfunction) 1, 3
• Avoid non-dihydropyridine calcium channel blockers (diltiazem, verapamil) – they worsen HF outcomes 3
• Avoid non-evidence-based beta-blockers (atenolol, labetalol, metoprolol tartrate) – no mortality benefit 3
• Avoid long-term continuous intravenous inotropes outside of palliative care or bridge to advanced therapies 5

Common Pitfalls to Avoid

1. Delaying simultaneous initiation – start all four classes immediately, not sequentially 1
2. Accepting suboptimal doses – only 1% of patients reach target doses in real-world practice; aggressive uptitration is essential 1, 6
3. Stopping medications for asymptomatic hypotension – patients with adequate perfusion tolerate SBP 80–100 mmHg 1
4. Overreacting to modest creatinine elevation – up to 30% increase above baseline is acceptable 1
5. Using metoprolol tartrate instead of metoprolol succinate – only the succinate formulation reduces mortality 3
6. Inadequate monitoring – check labs 1–2 weeks after each dose change 1
7. Attributing all adverse events to GDMT – 75–85% of HFrEF patients experience adverse events regardless of treatment 1

Monitoring Schedule

Week 0: Baseline labs (creatinine, eGFR, potassium, sodium, BNP/NT-proBNP), ECG, vital signs 1

Weeks 1–2,3–4,5–6,7–8: After each dose change:

• Blood pressure, heart rate, weight 1
• Creatinine, eGFR, potassium 1
• Assess volume status (edema, orthopnea, JVD) 3

Every 3–6 months: Repeat echocardiogram to assess EF trajectory 7

Early outpatient follow-up within 7–14 days after any medication change 1