What is the recommended guideline-directed medical and device therapy for a patient with severe systolic heart failure and an ejection fraction of about 20%?

Guideline-Directed Medical Therapy for Ejection Fraction 20%

A patient with an ejection fraction of 20% requires immediate initiation of all four foundational medication classes simultaneously—SGLT2 inhibitor, mineralocorticoid receptor antagonist (MRA), evidence-based beta-blocker, and ARNI (or ACE inhibitor if ARNI not tolerated)—along with loop diuretics for volume management, as this quadruple therapy provides approximately 61% reduction in all-cause mortality and adds 5.3 life-years compared to no treatment. 1

Immediate Initiation of Quadruple Therapy

The modern approach mandates starting all four medication classes as soon as possible after diagnosis, not sequentially: 1

First-Line Medications (Start Simultaneously)

• SGLT2 Inhibitor: Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily—no titration required, benefits occur within weeks, minimal blood pressure effect makes it ideal for immediate initiation 1, 2

• Mineralocorticoid Receptor Antagonist: Spironolactone 12.5-25 mg once daily, titrate to 50 mg daily at 8 weeks if tolerated—provides ≥20% mortality reduction and reduces sudden cardiac death 1, 3

• Evidence-Based Beta-Blocker: Carvedilol, metoprolol succinate, or bisoprolol starting at low dose (e.g., carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily)—provides 34% mortality reduction, the highest relative risk reduction among the four classes 1, 3

• ARNI (Preferred) or ACE Inhibitor: Sacubitril/valsartan 24/26 mg twice daily (if systolic BP >100 mmHg, eGFR >30 mL/min/1.73 m², potassium <5.2 mmol/L) provides ≥20% mortality reduction superior to ACE inhibitors 1, 4. If ARNI contraindicated or not tolerated, use ACE inhibitor (e.g., enalapril 2.5 mg twice daily) 3

Volume Management

• Loop Diuretics: 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—essential for congestion control but do not reduce mortality 1, 3

• Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state 1

Uptitration Strategy

Critical principle: Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 1

Sequencing Priority for Uptitration

1. Start SGLT2 inhibitor and MRA first since they have minimal blood pressure effects 1

2. Then add beta-blocker if heart rate >70 bpm or low-dose ARNI/ACE inhibitor 1

3. Uptitrate beta-blocker toward target dose (carvedilol 25 mg twice daily, metoprolol succinate 200 mg once daily, or bisoprolol 10 mg daily) using 2-week intervals if heart rate ≥70 bpm 1

4. Uptitrate ARNI to target dose of 97/103 mg twice daily over 4-8 weeks 1, 4

Target Doses from Clinical Trials

• Sacubitril/valsartan: 97/103 mg twice daily 4
• Carvedilol: 25 mg twice daily 1
• Metoprolol succinate: 200 mg once daily 1
• Bisoprolol: 10 mg once daily 1
• Spironolactone: 50 mg once daily 1
• Dapagliflozin: 10 mg once daily (no titration) 2
• Empagliflozin: 10 mg once daily (no titration) 1

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. 1

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

Step 1: Address reversible non-HF causes first 1

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 1
• Discontinue other non-essential BP-lowering medications 1
• Evaluate for dehydration, infection, or acute illness 1

Step 2: Non-pharmacological interventions 1

• Compression leg stockings for orthostatic symptoms 1
• Exercise and physical training programs 1
• Adequate salt and fluid intake if not volume overloaded 1
• Space out medication administration throughout the day 1

Step 3: If symptoms persist, reduce GDMT in this specific order 1

• If heart rate >70 bpm: reduce ACE inhibitor/ARB/ARNI dose first 1
• If heart rate <60 bpm: reduce beta-blocker dose first 1
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1

Monitoring Requirements

• Blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1

• Potassium levels require close monitoring with MRAs—if hyperkalemia develops, consider potassium binders (patiromer) rather than discontinuing life-saving medications 1

• Serial monitoring of natriuretic peptide levels can be useful during diuretic titration to ensure congestion does not worsen 3

Device Therapy Considerations

For a patient with EF 20% who remains symptomatic (NYHA Class II-III) despite ≥3 months of optimal medical therapy:

• Implantable Cardioverter-Defibrillator (ICD): Indicated for primary prevention if expected to survive >1 year with good functional status 1

• Cardiac Resynchronization Therapy (CRT): Indicated if in sinus rhythm with QRS duration ≥150 msec and left bundle branch block (LBBB) morphology 1

Critical Contraindications

• Never combine ACE inhibitor with ARNI due to angioedema risk 1

• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1

• Avoid diltiazem or verapamil in HFrEF as they increase risk of worsening heart failure 1

• Do not use non-evidence-based beta-blockers (e.g., atenolol, propranolol)—only carvedilol, metoprolol succinate, or bisoprolol have proven mortality benefit 1, 3

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start simultaneously, not sequentially 1

• Accepting suboptimal doses—clinical trials demonstrated benefits at target doses, not low doses 1

• 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 1

• Inadequate monitoring—more frequent monitoring required in elderly patients and those with chronic kidney disease 1

• Using metoprolol tartrate instead of metoprolol succinate—only the succinate formulation has proven mortality benefit 1

• Discontinuing RAASi after hypotension—associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy 1