What is the recommended management approach for heart failure with reduced ejection fraction (HFrEF)?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with symptomatic HFrEF should be started on quadruple therapy—consisting of an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated)—simultaneously at low doses as soon as the diagnosis is confirmed, along with loop diuretics for volume management. 1

Immediate Diagnostic Confirmation

Before initiating therapy, confirm the diagnosis with:

• Transthoracic echocardiography (TTE) to document LVEF ≤40% and assess myocardial structure 2
• Blood pressure measurement (supine and standing) to assess for orthostatic hypotension 2
• Heart rate assessment to guide beta-blocker dosing 2
• Renal function testing (eGFR, serum creatinine) and electrolytes (particularly potassium) to guide medication dosing 2
• Volume status assessment to determine diuretic requirements 2
• Evaluation for underlying causes including coronary artery disease, hypertension, and valvular disease 2

The Four Pillars of Pharmacological Therapy

Initiation Strategy: Simultaneous, Not Sequential

Start all four medication classes simultaneously at low doses within the first 4-6 weeks of diagnosis. 1, 2 The traditional step-by-step approach that delays one drug class until another is optimized is outdated and harmful. 2

Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment, and transitioning from traditional dual therapy to quadruple therapy can extend life expectancy by approximately 6 years. 3

Specific Medication Classes and Dosing

1. SGLT2 Inhibitors (Start First)

• Initiate immediately as they have minimal effect on blood pressure, provide rapid benefits within weeks, require no dose titration, and work independently of background therapy 1, 2
• Empagliflozin (10 mg daily) if eGFR ≥30 ml/min/1.73 m² OR Dapagliflozin (10 mg daily) if eGFR ≥20 ml/min/1.73 m² 2
• No titration required; benefits occur within weeks 1

2. Mineralocorticoid Receptor Antagonists (Start Concurrently)

• Spironolactone 12.5-25 mg daily OR Eplerenone 25 mg daily 3
• Provide at least 20% reduction in mortality risk 1, 3
• Minimal BP-lowering effects 2
• Monitor potassium and creatinine closely; exclude patients with baseline serum creatinine >2.5 mg/dL or potassium >5.0 mEq/L 4
• Uptitrate to target doses (spironolactone 25-50 mg daily, eplerenone 50 mg daily) with monitoring every 1-2 weeks 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 3

3. Beta-Blockers

• Evidence-based options: Carvedilol, metoprolol succinate (extended-release), or bisoprolol 5, 1
• Provide at least 20% reduction in mortality and decrease sudden cardiac death 1, 3
• Start at low dose if heart rate >70 bpm 2
• Selective β₁ receptor blockers (metoprolol succinate, bisoprolol) preferred in patients with borderline blood pressure due to lesser BP-lowering effects 2
• Uptitrate every 1-2 weeks to target doses 3

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors for patients with NYHA class II-III symptoms 1, 2
• Start at 24/26 mg or 49/51 mg twice daily, target dose 97/103 mg twice daily 1
• Provides at least 20% additional mortality reduction compared to ACE inhibitors 1, 3
• Critical: When switching from ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 3
• If ARNI not tolerated due to hypotension, use ACE inhibitor (enalapril, lisinopril, ramipril) or ARB (losartan, valsartan) 2, 3

Volume Management with Loop Diuretics

• Loop diuretics are essential for congestion control but do not reduce mortality 1
• Use furosemide, torsemide, or bumetanide 1
• Titrate based on urine output and congestion symptoms, not on a fixed schedule 1
• For hospitalized patients, initial IV dose should equal or exceed chronic oral daily dose 3
• Avoid over-diuresis, which may worsen hypotension and renal function 2

Managing Low Blood Pressure During Initiation

If systolic BP <100 mmHg but patient is asymptomatic or mildly symptomatic with adequate organ perfusion:

• Do not withhold GDMT 2
• Discontinue non-HF hypotensive medications (e.g., alpha-blockers, non-dihydropyridine calcium channel blockers) 2
• Prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then selective β₁ receptor blockers, then very low-dose ARNI or ACE inhibitors 2, 3
• Consider ivabradine if beta-blockers are not tolerated hemodynamically 2
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 3

Uptitration Protocol

• Uptitrate one medication at a time using small increments every 1-2 weeks until target or maximally tolerated doses are achieved 2
• Monitor at 1-2 weeks after each dose increment: blood pressure, heart rate, renal function (creatinine, eGFR), and potassium 2, 3
• More frequent monitoring needed in elderly patients and those with chronic kidney disease 3
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 3
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 3

Device Therapy Evaluation

Implantable Cardioverter-Defibrillator (ICD)

• Primary prevention indication: LVEF ≤35%, NYHA class II-III symptoms, ≥3 months of optimal medical therapy, and expected survival >1 year with good functional status 1, 2
• Wait at least 40 days post-myocardial infarction before ICD implantation 2
• Secondary prevention: After cardiac arrest or hemodynamically unstable ventricular tachycardia 1

Cardiac Resynchronization Therapy (CRT)

• Class I indication: LVEF ≤35%, NYHA class II-IV symptoms, sinus rhythm, and QRS ≥150 msec with left bundle branch block (LBBB) morphology 5, 1, 2
• CRT improves clinical outcomes in appropriately selected patients 5

Implementation Strategies and Follow-Up

• Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization 1, 3
• Nurse-led titration programs reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92) 3
• Pharmacist involvement improves GDMT adherence and dosing 1, 3
• Early follow-up within 7-14 days after medication adjustments is recommended 1, 3
• Cardiac rehabilitation and multidisciplinary team involvement improve patient outcomes 5

Critical Pitfalls to Avoid

• Never use the traditional step-by-step approach that delays one drug class until another is optimized 2
• Do not discontinue GDMT for asymptomatic hypotension or mild renal function changes 2
• Never combine ACE inhibitors with ARBs and MRAs (triple RAAS blockade) 2
• Never use diltiazem or verapamil in HFrEF patients (negative inotropes) 2
• Do not over-diurese 2
• Do not overreact to laboratory changes: modest creatinine elevation (up to 30% above baseline) is acceptable 3
• Do not prematurely discontinue GDMT: temporary symptoms of fatigue and weakness with dose increases usually resolve within days 3

Special Considerations

• For hospitalized patients: Continue GDMT except when hemodynamically unstable or contraindicated; in-hospital initiation substantially improves post-discharge medication use 3
• Patients with improved EF: Those with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen, as discontinuation may lead to clinical deterioration 3
• Health-related quality of life assessment: Use a validated tool (e.g., KCCQ-12) to assess patient outcomes 5