Diagnosis and Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF)
Diagnosis
Heart failure with reduced ejection fraction is diagnosed when patients present with symptoms of dyspnea, fatigue, or fluid retention AND have a left ventricular ejection fraction ≤40% on echocardiography. 1
Clinical Presentation
- Symptoms: Progressive dyspnea and fatigue that limit physical activity, with severity classified by NYHA functional class (Class II: symptoms with ordinary activity; Class III: symptoms with less-than-ordinary activity; Class IV: symptoms at rest). 1
- Physical examination findings: Peripheral edema, jugular venous distension, pulmonary rales, hepatomegaly (congestion signs); cool extremities, narrow pulse pressure, altered mental status in advanced cases (perfusion signs). 1
- Critical caveat: Signs may be absent in early HF or in patients already treated with diuretics, and symptom severity correlates poorly with ejection fraction—patients with very low LVEF may be asymptomatic while those with higher LVEF may have severe disability. 1
Diagnostic Testing
- Echocardiography: Confirms reduced LVEF ≤40% and assesses cardiac structure and function. 1
- Natriuretic peptides (BNP/NT-proBNP): Elevated levels support the diagnosis and help assess disease severity. 1
Treatment: Quadruple Foundational Therapy
All 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 (sacubitril/valsartan preferred over ACE inhibitor), along with loop diuretics for volume management—this combination reduces all-cause mortality by 61% and provides approximately 5.3 additional life-years compared to no treatment. 1
First-Line Medications (Start All Four Simultaneously)
1. SGLT2 Inhibitor (Start First)
- Dapagliflozin 10 mg once daily (if eGFR ≥20 mL/min/1.73 m²) OR Empagliflozin 10 mg once daily (if eGFR ≥30 mL/min/1.73 m²). 1
- Rationale: Reduces 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), making it ideal as the first agent. 1
- No titration required—benefits occur within weeks of initiation. 1
2. Mineralocorticoid Receptor Antagonist (Start Simultaneously with SGLT2i)
- Spironolactone 12.5-25 mg once daily OR Eplerenone 25 mg once daily (if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L). 1
- Rationale: Provides at least 20% mortality reduction and reduces sudden cardiac death, with minimal blood pressure effect allowing early initiation. 1
- Titration: Increase to spironolactone 50 mg daily or eplerenone 50 mg daily after 4 weeks if tolerated. 1
- Monitoring: Check potassium and creatinine at 1-2 weeks after initiation and after each dose increase. 1
3. Angiotensin Receptor-Neprilysin Inhibitor (ARNI) - Preferred Over ACE Inhibitor
- Sacubitril/valsartan 49/51 mg twice daily as starting dose. 1, 2
- Rationale: Provides at least 20% mortality reduction superior to ACE inhibitors, reducing cardiovascular death and HF hospitalization. 1, 3
- Titration: Double dose every 2-4 weeks to target maintenance dose of 97/103 mg twice daily as tolerated. 1, 2
- Critical requirement: If switching from ACE inhibitor, allow a 36-hour washout period to avoid angioedema risk. 1, 2
- Alternative if ARNI not tolerated: ACE inhibitor (enalapril 2.5 mg twice daily, titrate to 10-20 mg twice daily) OR ARB (valsartan 40 mg twice daily, titrate to 160 mg twice daily). 4, 5
4. Evidence-Based Beta-Blocker
- Carvedilol 3.125 mg twice daily OR Metoprolol succinate 12.5-25 mg once daily OR Bisoprolol 1.25 mg once daily. 1
- Rationale: Reduces mortality by at least 20% and decreases sudden cardiac death. 1
- Titration: Double dose every 2 weeks to target doses (carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily). 1, 4
- Critical warning: Only use evidence-based beta-blockers listed above—avoid diltiazem or verapamil as they increase risk of worsening HF and hospitalization. 1
Diuretics for Volume Management
- Loop diuretics are essential for congestion control but do not reduce mortality. 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
- Titration strategy: Adjust dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 1
Titration Strategy and Timeline
Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved, starting with SGLT2 inhibitor and MRA first (minimal BP effects), then beta-blocker, then ARNI. 1
Monitoring During Titration
- Check blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment. 1
- Acceptable changes: Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 1
- Potassium monitoring: Close monitoring required with MRAs; consider potassium binders (patiromer) if hyperkalemia develops rather than discontinuing life-saving medications. 1, 4
Managing Low Blood Pressure During Optimization
Never discontinue or reduce guideline-directed medical therapy (GDMT) for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 1
Algorithm for Hypotension Management
Step 1: Assess Blood Pressure and Symptoms
- If SBP ≥80 mmHg and asymptomatic: Continue GDMT without modification—asymptomatic hypotension is expected and beneficial. 1
- If SBP <80 mmHg OR symptomatic hypotension (dizziness, lightheadedness, syncope): Proceed to Step 2. 1
Step 2: Address Reversible Non-HF Causes First
- Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) and other non-essential BP-lowering medications. 1
- Evaluate for: Dehydration, infection, acute illness, excessive diuretic use. 1
- Reduce diuretic dose first rather than reducing life-saving GDMT. 1, 4
Step 3: Non-Pharmacological Interventions
- 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 medications throughout the day rather than taking simultaneously. 1
Step 4: Modify GDMT Only If Steps 1-3 Fail
- If heart rate >70 bpm: Reduce ACEi/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
- Critical warning: Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 1
Additional Therapies for Specific Subgroups
Ivabradine
- Indication: Patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker, who remain symptomatic. 1
- Dose: 2.5-5 mg twice daily, titrate to 7.5 mg twice daily. 1
- Caveat: Survival benefit is modest or negligible in the broad HFrEF population. 1
Hydralazine/Isosorbide Dinitrate
- Indication: Self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 1
- Dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily, titrate to hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily. 1
- Caveat: May be inferior to ACE inhibitors for mortality in non-Black populations. 1
Device Therapy
Implantable Cardioverter-Defibrillator (ICD)
- Indication: 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. 1, 4
- Also indicated for: Primary prevention in ischemic cardiomyopathy with mild symptoms; secondary prevention in patients who recovered from ventricular arrhythmia causing hemodynamic instability. 1
Cardiac Resynchronization Therapy (CRT)
- Indication: Symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and left bundle branch block (LBBB) morphology with LVEF ≤35% despite optimal medical therapy. 1
- Class I indication if: QRS ≥130 msec and LBBB in sinus rhythm. 1
Critical Contraindications and Medications to Avoid
- Never combine ACE inhibitor with ARNI due to angioedema risk—require 36-hour washout period when switching. 1, 2
- Avoid triple combination of ACE inhibitor + ARB + MRA due to increased risk of hyperkalemia and renal dysfunction. 1
- Avoid diltiazem or verapamil in HFrEF as they increase risk of worsening HF and hospitalization. 1
- Do not initiate statins specifically for HFrEF management in patients without other indications for lipid-lowering therapy. 1
Common Pitfalls to Avoid
- Delaying initiation of all four medication classes—start simultaneously, not sequentially. 1
- Accepting suboptimal doses—aggressively up-titrate to target doses using forced-titration approach. 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 in clinical trials. 1
- Inadequate monitoring—check renal function and electrolytes regularly during titration. 1
- Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol have proven mortality benefit. 1
- Down-titrating GDMT for modest creatinine increases—up to 30% increase is acceptable and should not prompt discontinuation. 1