What is the recommended treatment for a patient with heart failure with reduced ejection fraction (HFrEF)?

Heart Failure with Reduced Ejection Fraction (HFrEF) Treatment

Foundational Quadruple Therapy

All patients with HFrEF should be started on 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 diuretics for volume management. 1

This quadruple therapy approach provides approximately 73% mortality reduction over 2 years when all four classes are optimized. 1

The Four Pillars

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Reduce cardiovascular death and HF hospitalization regardless of diabetes status 1
• Minimal blood pressure effect, making them ideal first agents 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
• Once-daily dosing with no up-titration required 1

2. Mineralocorticoid Receptor Antagonists (Spironolactone or Eplerenone)

• Provide at least 20% mortality reduction and reduce sudden cardiac death 1
• Recommended for all symptomatic patients with LVEF ≤35% 1
• FDA-approved for NYHA Class III-IV heart failure to increase survival, manage edema, and reduce hospitalization 2
• Minimal blood pressure effect allowing early initiation 1
• Can be used if eGFR >30 ml/min/1.73 m² 1
• Require monitoring of renal function and serum potassium levels 1

3. Beta-Blockers (Carvedilol, Metoprolol Succinate, or Bisoprolol)

• Reduce mortality by at least 20% and decrease sudden cardiac death 1
• Should be initiated in clinically stable patients at low dose and gradually up-titrated to maximum tolerated dose 1
• Only use evidence-based beta-blockers; avoid non-evidence-based agents 1

4. ARNI (Sacubitril/Valsartan) - Preferred Over ACE Inhibitors

• Provides at least 20% mortality reduction, superior to ACE inhibitors 1
• FDA-approved to reduce cardiovascular death and hospitalization in adult patients with chronic HFrEF 3
• Preferred treatment over ACE inhibitors for symptomatic patients 1
• Actually reduces hyperkalemia risk when combined with MRAs compared to ACE inhibitors plus MRAs 1
• If ARNI not tolerated, use ACE inhibitor or ARB 1

Diuretics for Volume Management

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

• 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 1

Initiation and Titration Strategy

Start SGLT2 inhibitor and MRA first, as they have minimal blood pressure effects, then add beta-blocker or very low-dose ARNI. 1

Step-by-Step Approach:

1. Week 0: Start SGLT2 inhibitor at full dose (no titration needed) and MRA at low dose 1
2. Week 1-2: Add low-dose beta-blocker if heart rate >70 bpm or low-dose ARNI 1
3. Weeks 2-8: Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1
4. 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

Managing Low Blood Pressure During Optimization

Do not withhold therapy for asymptomatic low BP with adequate perfusion. 1

Algorithm for Hypotension:

Step 1: Address reversible non-HF causes first 1

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

Step 2: Use non-pharmacological interventions 1

• Space out medication timing 1
• Exercise and physical training 1
• Compression leg stockings to minimize orthostatic drops 1

Step 3: Never down-titrate or stop GDMT for asymptomatic hypotension 1

• GDMT medications have proven efficacy and safety even in patients with SBP <110 mmHg 1
• SGLT2 inhibitors cause smallest BP decrease (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg) 1

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate:

• 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
• Can prolong survival but may be inferior to ACE inhibitors for mortality 1

Ivabradine:

• Consider 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

Vericiguat:

• May have a role in certain subgroups of HFrEF patients 4

Device Therapy

Implantable Cardioverter-Defibrillator (ICD):

• Recommended for patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, who are expected to survive >1 year with good functional status 1
• Indicated for primary prevention in ischemic cardiomyopathy with mild symptoms 1
• For secondary prevention in patients who recovered from ventricular arrhythmia causing hemodynamic instability 1

Cardiac Resynchronization Therapy (CRT):

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

Avoid these medications in HFrEF:

• Diltiazem or verapamil (increase risk of worsening heart failure and hospitalization) 1
• Non-evidence-based beta-blockers 1
• NSAIDs and most antiarrhythmic drugs 5

Monitoring Requirements

Check at baseline:

• Confirm HFrEF diagnosis (EF ≤40%) with NYHA class II-IV symptoms 1
• Verify eGFR >30 mL/min/1.73 m² 1
• Verify potassium <5.0 mEq/L before initiating MRA 1

Monitor at 1-2 weeks after each dose increment:

• Blood pressure 1
• Renal function (creatinine, eGFR) 1
• Serum potassium 1
• More frequent monitoring in elderly patients and those with chronic kidney disease 1

If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications. 1

Common Pitfalls to Avoid

The following errors significantly worsen outcomes: 1

• Delaying initiation of all four medication classes
• Accepting suboptimal doses without attempting titration
• Stopping medications for asymptomatic hypotension
• Inadequate monitoring of renal function and electrolytes
• Using non-evidence-based beta-blockers
• Discontinuing RAAS inhibitors after hyperkalaemia (associated with two to fourfold higher risk of subsequent adverse events) 1

Worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function. 1

Advanced Heart Failure Management

Refer patients with advanced HF who wish to prolong survival to a team specializing in HF. 1

Consider:

• Mechanical circulatory support for eligible patients 1
• Transcatheter mitral valve repair in specific cases 4
• Heart transplantation evaluation 4

Real-World Implementation Challenges

Target doses of all recommended drugs were simultaneously achieved in only 1% of eligible patients in real-world registries, with discontinuation rates as high as 55% for ACE inhibitors. 1

Withdrawal of ACE inhibitors/ARBs during heart failure hospitalization is associated with higher rates of postdischarge mortality (41.6% vs 28.2% at 1 year) and readmission, even after adjustment for severity of illness. 6

Patient education about transient dizziness as a side effect of life-prolonging drugs improves compliance. 1