What are the medical management options for a patient with severe left ventricular (LV) dysfunction and reduced ejection fraction (HFrEF)?

Medical Management of Severe Left Ventricular Dysfunction

All patients with severe LV dysfunction (LVEF <35%) should receive simultaneous initiation of four foundational medication classes—SGLT2 inhibitor, mineralocorticoid receptor antagonist (MRA), beta-blocker, and ARNI (or ACE inhibitor/ARB)—started at low doses and uptitrated every 1-2 weeks to target doses, as this quadruple therapy reduces mortality risk by approximately 73% over 2 years. 1, 2

Core Pharmacological Strategy

The Four Pillars of Guideline-Directed Medical Therapy (GDMT)

SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Start at full dose immediately—no titration required 1, 2
• Uniquely suited for early initiation because they do not lower blood pressure, do not affect heart rate, and require no dose adjustment 1
• Provide rapid clinical benefits within weeks of initiation, independent of background therapy 1
• Effective even with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 1
• Should be initiated first after hemodynamic stabilization in decompensated patients 1

Mineralocorticoid Receptor Antagonists

• Start 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, 2
• Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 1, 2
• Provides approximately 20-23% reduction in mortality risk, specifically reducing sudden cardiac death 3, 1, 2
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 2
• Monitor potassium and creatinine closely during uptitration 2

Beta-Blockers (Only Three Proven Agents)

• Use only carvedilol, metoprolol succinate, or bisoprolol—do not substitute with other beta-blockers 3, 2
• Provide approximately 35% reduction in mortality with specific anti-arrhythmic effects that reduce sudden death 3
• Start at low doses and uptitrate to target doses every 1-2 weeks 2
• Initiate if heart rate >70 bpm and patient tolerates it hemodynamically 1

ARNI (Sacubitril/Valsartan) - Preferred First-Line

• Preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk 2
• Start at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 2
• Critical safety requirement: observe strict 36-hour washout period when switching from ACE inhibitor to avoid angioedema 2
• If ARNI not tolerated or available, use ACE inhibitors (reduce mortality by 15-25%) or ARBs 3, 2

Implementation Strategy

Simultaneous Initiation Protocol

• Start all four medication classes simultaneously at low initial doses rather than sequential titration 1, 2
• This approach extends life expectancy by approximately 6 years compared to traditional dual therapy 2
• Uptitrate every 1-2 weeks until target doses achieved 1, 2
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2

Prioritization During Uptitration

• If eGFR >30 mL/min/1.73m² and heart rate >60 bpm, prioritize ARNI/ACE inhibitor/ARB uptitration 2
• If blood pressure is low but perfusion adequate, prioritize SGLT2 inhibitors and MRAs first (minimal BP impact), then beta-blockers, then ARNI/ACE inhibitor/ARB 2

Managing Common Barriers to Optimal Therapy

Hypotension Management

• Asymptomatic low blood pressure should never prompt GDMT reduction—patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 2
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria) 2
• Reduce diuretics first if low blood pressure occurs in the absence of congestion, rather than stopping foundational GDMT 1
• Symptomatic hypotension (dizziness, fatigue) can usually be managed through patient education and spacing out medications 1

Renal Function Changes

• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt GDMT discontinuation 1, 2
• Temporary reduction or hold only if substantial renal deterioration occurs 2

Hyperkalemia Management

• Monitor potassium closely with MRA initiation and uptitration 2
• Adjust MRA dose or consider potassium binders rather than discontinuing therapy 2

Additional Therapies

Loop Diuretics

• Add only if fluid overload is present—they provide no mortality benefit 2
• Titrate based on symptoms and volume status, not as routine therapy 2

Ivabradine

• Consider if heart rate remains ≥70 bpm despite maximally tolerated beta-blocker therapy 4
• Reduces risk of hospitalization for worsening heart failure (hazard ratio 0.82) 4
• Start at 5 mg twice daily, adjust to maintain resting heart rate between 50-60 bpm 4
• Requires stable NYHA class II-IV heart failure with LVEF ≤35% 4

Vericiguat

• Consider for higher-risk patients with worsening HFrEF (LVEF <45%, NYHA class II-IV, elevated natriuretic peptides, recent HF hospitalization or IV diuretic therapy) who remain symptomatic despite GDMT 2
• Reduced cardiovascular death or HF hospitalization by 10% (HR 0.90) 2
• Avoid in patients with NT-proBNP >5314 pg/mL (highest quartile)—no benefit demonstrated 2

Hydralazine/Isosorbide Dinitrate

• Has a role in certain patients with HFrEF, particularly self-identified Black patients 5

Special Clinical Scenarios

Acute Decompensated Heart Failure

• Continue GDMT except when hemodynamically unstable or contraindicated 2, 6
• Initiate GDMT after ≥24 hours of hemodynamic stabilization with adequate organ perfusion 1, 2
• In-hospital initiation substantially improves post-discharge medication use 2
• Start with SGLT2 inhibitor first (safest in hemodynamically vulnerable patients), then add MRA if eGFR >25-30 ml/min/1.73 m² and potassium <5.0 mEq/L 1

Recovered Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 2, 7
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 2
• HF-recovered patients (LVEF improving from <45% to ≥45%) have significantly better outcomes than persistent HFrEF, but still require ongoing therapy 7

Severe LV Dysfunction (LVEF ≤25%)

• More than half of patients with chronic HFrEF have LVEF ≤25% 8
• These patients have higher hazards for death (HR 1.24), all-cause hospitalization (HR 1.21), and HF hospitalization (HR 1.25) through 5 years compared to LVEF 26-35% 8
• Require aggressive GDMT optimization and closer monitoring 8

Surgical/Interventional Considerations

Coronary Revascularization

• CABG or medical therapy is reasonable to improve morbidity and cardiovascular mortality for patients with severe LV dysfunction (EF <35%), HF, and significant CAD 3
• CABG may be considered in patients with ischemic heart disease, severe LV systolic dysfunction (EF <35%), and operable coronary anatomy whether or not viable myocardium is present 3
• Can be performed relatively safely despite advanced LV dysfunction with careful patient selection 9

Valve Interventions

• Surgical aortic valve replacement is reasonable for patients with critical aortic stenosis and predicted surgical mortality ≤10% 3
• Transcatheter aortic valve replacement is reasonable for patients with critical aortic stenosis deemed inoperable 3
• Transcatheter mitral valve repair for functional mitral insufficiency is of uncertain benefit and should only be considered after careful candidate selection with background GDMT 3

Device Therapy

• Implantable cardiac defibrillators (ICDs) benefit patients with more severe LV dysfunction, particularly of ischemic etiology 5
• Cardiac resynchronization therapy (CRT) benefits patients with interventricular dyssynchrony 5
• Mechanical circulatory support for cardiogenic shock or advanced HF as bridge to transplantation 3

Systems of Care

Multidisciplinary Approach

• Effective care coordination with attention to care transitions should be deployed for every patient with chronic HF 3
• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration, reduce all-cause mortality (OR 0.66), and reduce HF hospitalizations 2
• Nurse-led titration programs are effective for achieving target doses 2
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients 2

Follow-up Strategy

• Schedule early follow-up visit within 7-14 days and early telephone follow-up within 3 days of hospital discharge 3
• Every patient should have a clear, detailed, evidence-based plan of care ensuring achievement of GDMT goals 3

Critical Pitfalls to Avoid

• Do not wait to achieve target dosing of one medication before initiating the next—this delays life-saving therapy 1, 2
• Do not overreact to asymptomatic laboratory changes—modest creatinine increases and asymptomatic hypotension are acceptable 1, 2
• Do not discontinue GDMT in patients whose ejection fraction improves—continue all HFrEF medications 2, 7
• Do not use beta-blockers other than the three proven agents (carvedilol, metoprolol succinate, bisoprolol) 3, 2
• Do not delay MRA initiation waiting for "perfect" potassium or renal function—modest abnormalities are manageable 1
• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT 2