What is the guideline-directed initial treatment for a patient with heart failure with reduced ejection fraction?

Guideline-Directed Initial Treatment for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF (LVEF ≤40%) should immediately start 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

The Quadruple Therapy Regimen

This comprehensive approach provides approximately 73% mortality reduction over 2 years and adds 5.3 additional life-years compared to no treatment, with a 61% relative reduction in all-cause mortality (HR 0.39,95% CI: 0.32-0.49). 2, 3

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily should be initiated immediately. 1, 2
• These agents reduce cardiovascular death and HF hospitalization regardless of diabetes status, with minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg). 2, 3
• No dose titration is required—the 10 mg dose provides maximal benefit. 3
• Can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin, or ≥20 mL/min/1.73 m² for dapagliflozin. 3

2. Mineralocorticoid Receptor Antagonists (Start First)

• Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily should be initiated immediately. 4, 3
• These provide at least 20% mortality reduction and reduce sudden cardiac death, with minimal blood pressure effect allowing early initiation. 2, 3
• Titrate to target dose of spironolactone 50 mg daily or eplerenone 50 mg daily over 4-8 weeks. 3
• Can be used if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L. 3

3. Beta-Blockers

• Use only evidence-based beta-blockers: carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily. 4, 2, 3
• These reduce mortality by at least 20% (up to 34% in some analyses) and decrease sudden cardiac death. 2, 3
• Titrate every 1-2 weeks to target doses: carvedilol 25 mg twice daily (50 mg twice daily if >85 kg), metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily. 4, 3

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan (ARNI) is strongly preferred over ACE inhibitors, providing superior mortality reduction of at least 20% compared to ACE inhibitors. 4, 2, 3
• Start sacubitril/valsartan 24 mg/26 mg twice daily (or 49 mg/51 mg twice daily if not on prior ACE inhibitor/ARB). 4, 2
• Titrate to target dose of 97 mg/103 mg twice daily over 3-6 weeks. 3
• If ARNI not tolerated, use enalapril 2.5-5 mg twice daily, lisinopril 2.5-5 mg once daily, or losartan 25-50 mg once daily, titrating to target doses. 4
• Wait 36 hours after stopping ACE inhibitor before starting ARNI to avoid angioedema. 3

5. Loop Diuretics for Volume Management

• 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. 3
• Diuretics are essential for congestion control but do not reduce mortality—they must always be combined with the four foundational classes. 4, 3
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 3

Initiation Strategy: Start All Four Classes Simultaneously

The modern approach is to start all four medication classes at once, not sequentially. 1, 2, 3 This represents a major shift from older guidelines that recommended sequential addition.

• Begin with SGLT2 inhibitor and MRA first since they have minimal blood pressure effects. 2, 3
• Add beta-blocker and ARNI/ACE inhibitor simultaneously or within days. 2, 3
• This aggressive approach is supported by the 2022 ACC/AHA/HFSA guidelines and provides the greatest mortality benefit. 1

Titration Protocol

• Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 2, 3
• Prioritize SGLT2 inhibitor and MRA first (no titration needed for SGLT2i), then beta-blocker, then ARNI. 2, 3
• Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment. 3
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 3

Managing Low Blood Pressure During Optimization

This is the most common barrier to GDMT optimization, but asymptomatic hypotension with adequate perfusion is NOT a contraindication to therapy. 2, 3

• Never discontinue or reduce GDMT for asymptomatic hypotension (even if SBP <100 mmHg) as long as perfusion is adequate. 2, 3
• GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2, 3
• For symptomatic hypotension (SBP <80 mmHg or major symptoms), address reversible non-HF causes first: stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, and evaluate for dehydration or infection. 2, 3
• If symptoms persist, reduce GDMT in this specific order: if heart rate >70 bpm, reduce ARNI/ACE inhibitor dose first; if heart rate <60 bpm, reduce beta-blocker dose first. 3
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects). 3

Critical Contraindications and Medications to Avoid

• Never combine ACE inhibitor with ARNI due to angioedema risk. 3
• Never use triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk. 4, 3
• Avoid diltiazem or verapamil in HFrEF—they increase risk of worsening heart failure and hospitalization. 4, 3
• Avoid non-evidence-based beta-blockers (atenolol, metoprolol tartrate)—only use carvedilol, metoprolol succinate, or bisoprolol. 3

Monitoring Requirements

• Initial phase (first 3 months): Check blood pressure, renal function (creatinine, eGFR), and electrolytes (potassium) at 1-2 weeks after each dose change. 3
• Maintenance phase: Monitor every 6 months once stable on target doses. 2
• If hyperkalemia develops (K+ >5.5 mEq/L), consider potassium binders (patiromer) rather than discontinuing life-saving medications. 3
• Discontinuing RAAS inhibitors after hyperkalemia is associated with two to fourfold higher risk of subsequent adverse events. 3

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start simultaneously, not sequentially. 3
• Accepting suboptimal doses due to unfounded BP concerns—clinical trials demonstrated benefits at target doses, not low doses. 3
• 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. 3
• Inadequate monitoring leading to missed opportunities for dose optimization. 4
• Using non-evidence-based beta-blockers instead of carvedilol, metoprolol succinate, or bisoprolol. 3

Device Therapy Considerations

Once medical therapy is optimized for at least 3 months, evaluate for device therapy:

• ICD for primary prevention: Indicated for symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy, expected to survive >1 year with good functional status. 4, 3
• CRT: Indicated for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and LBBB morphology with LVEF ≤35% despite optimal medical therapy. 4, 3

Additional Therapies for Specific Subgroups

• Hydralazine/isosorbide dinitrate: For self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy (hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily, titrate to 75 mg/40 mg three times daily). 3
• Ivabradine: Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker (start 2.5-5 mg twice daily). 3