What is the recommended management for an adult patient with chronic heart failure with reduced ejection fraction?

Management of Chronic Heart Failure with Reduced Ejection Fraction

All adult patients with symptomatic HFrEF (NYHA class II–IV) should immediately start four foundational medication classes simultaneously: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor if ARNI not tolerated), along with loop diuretics for volume management—this quadruple therapy reduces all-cause mortality by 61% and adds approximately 5.3 life-years compared to no treatment. 1

Immediate Initiation: The Four Pillars of HFrEF Therapy

1. SGLT2 Inhibitor (Start First)

• Begin dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily immediately upon diagnosis. 1, 2
• These agents reduce cardiovascular death and HF hospitalization regardless of diabetes status, with benefits appearing within weeks. 1
• No dose titration required—the starting dose is the therapeutic dose. 2
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making them ideal first agents even in borderline hypotension. 2
• Can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin or ≥20 mL/min/1.73 m² for dapagliflozin. 2

2. Mineralocorticoid Receptor Antagonist (Start Simultaneously)

• Start spironolactone 12.5–25 mg once daily, titrating to target dose of 50 mg daily after 2–4 weeks. 1, 2
• Provides at least 20% mortality reduction and reduces sudden cardiac death. 3, 1
• Minimal blood pressure effect allows early initiation alongside SGLT2 inhibitor. 1
• Requires eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L before starting. 3, 1
• If gynecomastia develops (occurs in ~10% of patients), switch to eplerenone. 2

3. Beta-Blocker (Evidence-Based Agents Only)

• Use only carvedilol, metoprolol succinate, or bisoprolol—these three agents have proven mortality benefit. 3, 1, 2
• Start at low dose and titrate every 2 weeks to target: carvedilol 25 mg twice daily, metoprolol succinate 200 mg once daily, or bisoprolol 10 mg once daily. 1, 2
• Beta-blockers provide 34% mortality reduction, the highest relative risk reduction among the four medication classes. 2
• Critical: Do NOT use metoprolol tartrate (immediate-release)—only metoprolol succinate (extended-release) has demonstrated mortality benefit. 2

4. ARNI (Sacubitril/Valsartan) or ACE Inhibitor

• For symptomatic patients (NYHA II–IV), sacubitril/valsartan is preferred over ACE inhibitors, providing superior 20% mortality reduction. 1, 2, 4
• Starting dose: 49/51 mg twice daily, titrating to target 97/103 mg twice daily after 2–4 weeks. 1, 4
• If switching from ACE inhibitor, allow 36-hour washout period to avoid angioedema. 4
• If ARNI not tolerated, use ACE inhibitor (enalapril 10 mg twice daily target) or ARB (losartan 150 mg daily target). 3
• Never combine ACE inhibitor with ARNI—this causes angioedema. 1, 2

Diuretic Management for Volume Control

• Loop diuretics are essential for congestion but do not reduce mortality. 3, 1
• Starting doses: 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. 1
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state. 2
• Thiazides can be used if eGFR >30 mL/min/1.73 m², but switch to loop diuretics below this threshold. 1

Titration Strategy: Aggressive but Systematic

The key to maximizing survival is reaching target doses, not just starting medications. 1, 2

Sequencing for Optimal Tolerability

1. Start SGLT2 inhibitor and MRA first (minimal BP effects). 1, 2
2. Add beta-blocker after 1–2 weeks, titrating every 2 weeks if heart rate ≥70 bpm and SBP >80 mmHg. 1, 2
3. Initiate or up-titrate ARNI/ACE inhibitor after beta-blocker is stable. 1, 2
4. Increase one drug at a time every 1–2 weeks using small increments until target or maximally tolerated dose achieved. 1, 2

Monitoring During Titration

• Check blood pressure, renal function, and electrolytes at baseline, 1–2 weeks after each medication adjustment, at 3 months, then every 6 months. 1
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 2
• If hyperkalemia develops (K+ >5.5 mEq/L), consider potassium binders (patiromer) rather than stopping life-saving medications. 1, 2

Managing Low Blood Pressure During Optimization

Asymptomatic hypotension with adequate perfusion is NOT a contraindication to GDMT—never discontinue or reduce therapy for SBP >80 mmHg without symptoms. 1, 2

Algorithmic Approach to Hypotension

1. If SBP 80–110 mmHg and asymptomatic: Continue aggressive up-titration of all four medication classes. 1, 2
2. If symptomatic hypotension (SBP <80 mmHg or major symptoms):
   • First, address reversible non-HF causes: stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration/infection. 2
   • Second, try non-pharmacological interventions: compression leg stockings, exercise training, adequate salt/fluid intake if not volume overloaded. 2
   • Third, 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. Always maintain SGLT2 inhibitor and MRA. 2

Critical Contraindications and Medications to Avoid

Absolute Contraindications

• Never combine ACE inhibitor + ARB + MRA (triple RAAS blockade causes life-threatening hyperkalemia and renal dysfunction). 3, 1, 2
• Never combine ACE inhibitor with ARNI (angioedema risk). 1, 2, 4
• Avoid diltiazem and verapamil in HFrEF—these non-dihydropyridine calcium channel blockers worsen heart failure and increase hospitalization risk. 1, 2

Medications That Interfere with GDMT

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) as they cause hypotension and compromise GDMT optimization. 2
• Consider 5-alpha reductase inhibitors (finasteride, dutasteride) for benign prostatic hyperplasia instead. 2
• Avoid NSAIDs—they worsen renal function and blunt ACE inhibitor efficacy. 3

Additional Therapies for Specific Subgroups

Ivabradine (If Heart Rate Remains Elevated)

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker. 1, 2
• Starting dose: 2.5–5 mg twice daily, titrating to 7.5 mg twice daily. 1
• Survival benefit is modest compared to the four foundational classes. 2

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III–IV symptoms despite optimal therapy. 1, 2
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily, titrating to 75 mg/40 mg three times daily. 1
• Also use if patient intolerant of both ACE inhibitors and ARBs. 3

Digoxin

• No mortality benefit but may reduce hospitalizations in symptomatic patients already on optimal therapy. 5
• Use lowest effective dose (0.125 mg daily) to minimize toxicity risk. 5

Device Therapy Timing

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for primary prevention in patients with LVEF ≤35% despite ≥3 months of optimal medical therapy, NYHA class II–III, and expected survival >1 year. 1, 2
• Do NOT implant within 40 days of myocardial infarction—no benefit during this period. 1

Cardiac Resynchronization Therapy (CRT)

• Indicated for patients in sinus rhythm with QRS ≥150 msec, LBBB morphology, and LVEF ≤35% despite optimal medical therapy. 1, 2
• CRT reduces all-cause mortality and hospitalization but increases adverse events. 3

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—start simultaneously, not sequentially. 1, 2
2. Accepting suboptimal doses—clinical trials demonstrated benefits at target doses, not low doses. 1, 2
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. 2
4. Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, and bisoprolol reduce mortality. 1, 2
5. Inadequate monitoring—check renal function and electrolytes 1–2 weeks after each dose change. 1, 2
6. Discontinuing RAASi after hyperkalemia—this is associated with two- to fourfold higher risk of subsequent adverse events; use potassium binders instead. 2

Heart Failure with Preserved Ejection Fraction (HFpEF)

Insufficient evidence exists to recommend specific pharmacologic therapies for HFpEF beyond treatment of comorbid conditions and diuretic therapy for fluid retention. 3

• Offer exercise-based rehabilitation programs to all HFpEF patients with stable symptoms. 3
• In selected HFpEF patients, spironolactone may reduce heart failure hospitalizations. 2