What are the initial treatment guidelines for a patient with heart failure with reduced ejection fraction (HFrEF)?

Heart Failure with Reduced Ejection Fraction (HFrEF) Management

Foundational Quadruple Therapy - Start Immediately at Diagnosis

All patients with HFrEF (LVEF ≤40%) and NYHA class II-IV symptoms should start four 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

This combination provides approximately 73% mortality reduction over 2 years and adds 5.3 additional life-years compared to no treatment 1. The all-cause mortality reduction reaches 61% (HR 0.39,95% CI: 0.32-0.49) when all four classes are used together 1.

The Four Pillars:

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily OR empagliflozin 10 mg once daily 1
• Reduces cardiovascular death and HF hospitalization regardless of diabetes status 1
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months) 1
• Benefits occur within weeks of initiation 1
• Can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin, or ≥20 mL/min/1.73 m² for dapagliflozin 1

2. Mineralocorticoid Receptor Antagonists (Start First)

• Spironolactone 12.5-25 mg once daily OR eplerenone 25 mg once daily 1
• Provides at least 20% mortality reduction and reduces sudden cardiac death 1
• Minimal blood pressure effect, allowing early initiation 1
• Can be used if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L 1
• Target dose: spironolactone 25-50 mg daily, eplerenone 50 mg daily 1

3. Angiotensin Receptor-Neprilysin Inhibitor (ARNI) - Preferred Over ACE Inhibitors

• Sacubitril/valsartan (Entresto) is superior to ACE inhibitors, providing at least 20% mortality reduction compared to enalapril 1, 2
• Starting dose: 49/51 mg twice daily for patients on high-dose ACE inhibitors; 24/26 mg twice daily for those on low/medium-dose ACE inhibitors/ARBs or treatment-naïve 2
• Target dose: 97/103 mg twice daily 2
• Critical: 36-hour washout period required when switching from ACE inhibitor to avoid angioedema; no washout needed from ARB 2
• Reduces cardiovascular death or HF hospitalization by 20% compared to enalapril (HR 0.8; 95% CI 0.73-0.87) 3

Alternative if ARNI not tolerated:

• ACE inhibitor: Lisinopril 20-35 mg daily OR enalapril 10-20 mg twice daily 4
• ARB: Valsartan 160 mg twice daily (only if ACE inhibitor causes cough or angioedema) 1

4. Evidence-Based Beta-Blockers

• Carvedilol 25-50 mg twice daily OR metoprolol succinate 200 mg once daily OR bisoprolol 10 mg once daily 1
• Reduces mortality by at least 20% and decreases sudden cardiac death 1
• Start at low dose and up-titrate gradually 1

Initiation Strategy - Critical Sequencing

Start SGLT2 inhibitor and MRA first (same day) because they have minimal blood pressure effects, then add beta-blocker or very low-dose ARNI within 1-2 weeks 1. This approach minimizes hypotension risk while rapidly achieving mortality benefit.

Titration Protocol:

• Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1
• Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1

Volume Management with Diuretics

Loop diuretics are essential for congestion control but do not reduce mortality 1:

• Furosemide 20-40 mg once or twice daily 1
• Torsemide 10-20 mg once daily 1
• 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 the lowest dose that maintains this state 1.

Managing Low Blood Pressure - Do NOT Stop GDMT

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion 1. GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg 1.

Algorithm for Symptomatic Hypotension (SBP <80 mmHg or major symptoms):

Step 1: Address reversible non-HF causes first 1

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 1
• Discontinue other non-essential BP-lowering medications 1
• Evaluate for dehydration, infection, or acute illness 1

Step 2: Non-pharmacological interventions 1

• Compression leg stockings for orthostatic symptoms 1
• Space out medication timing throughout the day 1
• Exercise and physical training programs 1

Step 3: If symptoms persist, reduce GDMT in this specific order 1:

• If heart rate >70 bpm: reduce ARNI/ACE inhibitor/ARB dose first 1
• If heart rate <60 bpm: reduce beta-blocker dose first 1
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1

Additional Therapies for Specific Subgroups

Ivabradine 1:

• Add if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1
• Starting dose: 2.5-5 mg twice daily 1
• Survival benefit is modest or negligible in broad HFrEF population 1

Hydralazine/Isosorbide Dinitrate 1:

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• May be inferior to ACE inhibitors for mortality 1

Device Therapy Indications

Implantable Cardioverter-Defibrillator (ICD) 1:

• Primary prevention: symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy, expected survival >1 year with good functional status 1
• Secondary prevention: patients who recovered from ventricular arrhythmia causing hemodynamic instability 1

Cardiac Resynchronization Therapy (CRT) 1:

• 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 1:

• ACE inhibitor with ARNI (risk of angioedema) 1
• ACE inhibitor + ARB + MRA (risk of hyperkalemia and renal dysfunction) 1

Avoid in HFrEF 1:

• Diltiazem or verapamil (increase risk of worsening heart failure and hospitalization) 1
• Non-evidence-based beta-blockers 1
• NSAIDs 5
• Most antiarrhythmic drugs (except amiodarone when needed) 6

Monitoring Requirements

At baseline and 1-2 weeks after each dose change 1, 2:

• Blood pressure 2
• Serum creatinine and eGFR 2
• Serum potassium (caution when >5.0 mEq/L, particularly with MRA) 2

Hyperkalemia management: Consider potassium binders like patiromer rather than discontinuing life-saving medications 1. Discontinuing RAAS inhibitors after hyperkalemia is associated with two to fourfold higher risk of subsequent adverse events 1.

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes simultaneously 1
• Accepting suboptimal doses without attempting titration 1
• Stopping medications for asymptomatic hypotension 1
• Down-titrating GDMT before addressing reversible non-HF causes of hypotension 1
• Using non-evidence-based beta-blockers 1
• Inadequate monitoring of renal function and electrolytes 1
• Believing that medium-range doses provide most benefits of target doses (they do not) 2

Real-World Implementation Challenges

Target doses of all recommended drugs are simultaneously achieved in only 1% of eligible patients in real-world registries, with discontinuation rates as high as 55% for ACE inhibitors 1. Advanced age, female sex, lower blood pressure, and greater severity of HF are consistently associated with lower prescription or up-titration of GDMT 1. Aggressive forced-titration approach to target doses is essential to achieve optimal outcomes 1.