What are the management strategies for a patient with heart failure, including those with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF)?

Management of Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF, EF ≤40%) should receive simultaneous initiation of four foundational medication classes—ARNI (or ACEi/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—started as early as possible even at low doses with rapid up-titration to target doses within 2 months, as this quadruple therapy provides approximately 73% mortality reduction over 2 years. 1

Classification by Ejection Fraction

Heart failure is classified into distinct categories based on left ventricular ejection fraction 2:

• HFrEF (EF ≤40%): Systolic heart failure where efficacious therapies have been demonstrated in randomized controlled trials 2, 3
• HFmrEF (EF 41-49%): Borderline group with characteristics and outcomes similar to HFpEF 2
• HFpEF (EF ≥50%): Diastolic heart failure where fewer efficacious therapies exist, though recent evidence shows benefit with SGLT2 inhibitors 2

Management of HFrEF: The Quadruple Therapy Approach

Core Medications (All Four Classes Simultaneously)

1. ARNI (Sacubitril/Valsartan) - Preferred First-Line Agent

• Sacubitril/valsartan is superior to ACE inhibitors, providing at least 20% mortality reduction beyond ACEi alone 4, 1
• Start at 24/26 mg or 49/51 mg twice daily, target 97/103 mg twice daily 1
• If already on ACEi/ARB and tolerating it, switch to ARNI after 36-hour washout period 1
• Contraindicated with concurrent ACEi use due to angioedema risk 4
• Mechanism: Inhibits neprilysin (increasing natriuretic peptides) while blocking angiotensin II AT1 receptors 5

2. Evidence-Based Beta-Blockers

• Only carvedilol, metoprolol succinate, or bisoprolol reduce mortality by at least 20% and decrease sudden cardiac death 3, 4
• Start low (e.g., carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, bisoprolol 1.25 mg daily) 1
• Uptitrate every 1-2 weeks to target doses 1
• Non-evidence-based beta-blockers (atenolol, propranolol) should not be used 4

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone provide at least 20% mortality reduction and reduce sudden cardiac death 4, 1
• Indicated for all symptomatic patients with LVEF ≤35% 4
• Start spironolactone 12.5-25 mg daily, target 25-50 mg daily 1
• Requires eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L before initiation 3, 4
• FDA-approved for NYHA Class III-IV heart failure to increase survival, manage edema, and reduce hospitalization 6

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin reduce cardiovascular death and HF hospitalization regardless of diabetes status 3, 1
• Benefits occur within weeks of initiation with once-daily dosing and no up-titration required 1
• Minimal blood pressure effects (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg) 4
• Can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin or ≥20 mL/min/1.73 m² for dapagliflozin 4

Implementation Algorithm

Step 1: Simultaneous Initiation (Day 1)

• Start all four medication classes together at low doses rather than waiting to achieve target doses sequentially 1
• This approach achieves optimal treatment within 2 months versus traditional sequential titration taking 6-12 months 1
• Add loop diuretics (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) for congestion control 4

Step 2: Rapid Up-Titration

• Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 4, 1
• Prioritize SGLT2 inhibitor and MRA first (minimal BP effects), then beta-blocker, then ARNI 4
• Monitor blood pressure, heart rate, renal function, and electrolytes at 1-2 weeks after each dose increment 4

Step 3: Monitoring and Adjustments

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 4
• If hyperkalemia develops (K+ >5.5 mEq/L), consider potassium binders like patiromer rather than discontinuing life-saving medications 4
• Worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function 4

Managing Low Blood Pressure During Optimization

Critical Principle: Asymptomatic low blood pressure (even <90 mmHg systolic) without hypoperfusion is NOT a contraindication to guideline-directed medical therapy 4, 1

For Symptomatic Hypotension:

1. Address reversible non-HF causes first 4:

   • Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 4
   • Discontinue other non-essential BP-lowering medications 4
   • Evaluate for dehydration, infection, or acute illness 4

2. Non-pharmacological interventions 4:

   • Space out medication timing throughout the day
   • Encourage exercise and physical training
   • Use compression leg stockings to minimize orthostatic drops

3. Medication sequencing for low BP patients 4:

   • Start SGLT2 inhibitor and MRA first (minimal BP effects)
   • Then add low-dose beta-blocker if heart rate >70 bpm
   • Finally add very low-dose ARNI (24/26 mg twice daily)

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 2, 4
• Start hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 4
• Can be useful in patients who cannot tolerate ACEi/ARB/ARNI 2

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 4
• Start 2.5-5 mg twice daily 4
• Survival benefit is modest or negligible in broad HFrEF population 4

Digoxin

• Can be beneficial for symptom control but does not reduce mortality 2
• Consider for persistent symptoms despite optimal therapy 2

Anticoagulation

• Patients with chronic HF and permanent/persistent/paroxysmal atrial fibrillation plus additional risk factor for cardioembolic stroke should receive chronic anticoagulation 2
• Anticoagulation is not recommended in HFrEF without AF, prior thromboembolic event, or cardioembolic source 2

Device Therapies

Implantable Cardioverter-Defibrillator (ICD)

• Recommended for primary prevention if LVEF ≤35% despite ≥3 months of optimal GDMT, NYHA Class II-III symptoms, and life expectancy >1 year with good functional status 4, 1
• Indicated for secondary prevention in patients who survived ventricular arrhythmia causing hemodynamic instability 4

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 4, 1
• Class I indication if QRS ≥130 msec and LBBB in sinus rhythm 4

Critical Contraindications and Medications to Avoid

Never combine 4:

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

Avoid in HFrEF 2, 4:

• Diltiazem or verapamil (increase risk of worsening HF and hospitalization)
• Non-evidence-based beta-blockers
• Statins initiated specifically for HF management without other lipid-lowering indication 4
• Long-term infusion of positive inotropic drugs except as palliation 2

Acute Decompensated HFrEF Management

Immediate Actions:

• Start IV loop diuretics immediately without delay, with initial IV dose equal to or exceeding chronic oral daily dose 2, 1
• Continue GDMT except in cases of hemodynamic instability or contraindications 2
• Thrombosis/thromboembolism prophylaxis is mandatory 2

Diuretic Strategies:

• If diuresis inadequate, give higher doses of IV loop diuretics or add second diuretic (thiazide) 2
• Low-dose dopamine infusion may be considered with loop diuretics to improve diuresis 2
• Ultrafiltration may be considered for obvious volume overload 2

Beta-Blocker Management:

• Initiation at low dose is recommended after optimization of volume status and discontinuation of IV inotropes 2

Management of HFpEF (EF ≥50%)

Evidence-Based Pharmacological Therapy

SGLT2 Inhibitors - First-Line Therapy

• SGLT2 inhibitors reduce composite cardiovascular events driven by reduction in HF hospitalizations in HFpEF 2, 7
• Empagliflozin demonstrated efficacy in EMPEROR-Preserved trial regardless of ejection fraction 8
• This represents the most significant therapeutic advance for HFpEF in recent years 2

Diuretics

• All guidelines concordantly recommend diuretics for symptomatic relief of congestion 2
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 4

Mineralocorticoid Receptor Antagonists

• Aldosterone blocking agents show benefit in specific HFpEF populations 9
• Consider for patients with lower-range EF within HFpEF spectrum 2

ARNI (Sacubitril/Valsartan)

• Results in smaller reductions in HF hospitalizations among HFpEF patients compared to HFrEF 7
• In PARAGON-HF, decreased NT-proBNP by 24% at Week 16 and 19% at Week 48 compared to valsartan 5

Non-Pharmacological Management

Cardiac Rehabilitation and Exercise

• Five guidelines recommend cardiac rehabilitation despite less data in HFpEF than HFrEF 2
• Improves quality of life though evidence for hospitalization reduction is limited 2
• REHAB-HFpEF and REACH-HFpEF trials are ongoing 2

Risk Factor and Comorbidity Management

• Treatment of hypertension, diabetes, obesity, atrial fibrillation, and ischemic heart disease is crucial 2, 10
• Lifestyle modification including sodium restriction and fluid management 2

Multidisciplinary Team Involvement

• Wider MDT is crucial for personalized treatment including patient education, psychosocial support, and exercise training 2
• Early palliative care involvement for symptom management and quality of life 2

Diagnostic Considerations for HFpEF

Natriuretic Peptide Screening:

• AHA/ACC/HFSA discuss utility of NPs in screening at-risk patients (BNP >50 pg/L, NT-proBNP >125 pg/L) 2
• Important caveat: proportion of HFpEF patients have normal NP levels 2

Advanced Diagnostics:

• Exercise echocardiography, invasive hemodynamics, and investigations for "HFpEF mimickers" may be required 7
• Cardiac imaging plays the largest role in arriving at specific diagnoses within HFpEF umbrella 9
• Specific therapies emerging for specific etiologies (hypertrophic cardiomyopathy, cardiac amyloidosis) 9

Management of HFmrEF (EF 41-49%)

SGLT2 Inhibitors:

• Beneficial in decreasing HF hospitalizations and cardiovascular mortality for HFmrEF 3

Other Evidence-Based Therapies:

• Evidence-based beta-blockers, ARNI, ACEi/ARB, and MRAs should be considered, particularly for patients with LVEF on lower end of spectrum 3

Advanced Heart Failure (Stage D) Management

Referral Criteria to HF Specialty Team 1:

• Persistent NYHA class III-IV symptoms despite optimal GDMT
• Recurrent hospitalizations for HF
• Need for continuous or intermittent inotropic support
• Consideration for advanced therapies (transplant, mechanical circulatory support)

Advanced Therapies:

• Cardiac transplantation evaluation is indicated for carefully selected stage D HF patients despite GDMT, device, and surgical management 2
• Durable mechanical circulatory support is reasonable to prolong survival for carefully selected patients 2
• Nondurable MCS reasonable as "bridge to recovery" or "bridge to decision" for acute profound hemodynamic compromise 2

Palliative Care:

• Should start early in disease trajectory with referral to specialist palliative care if needs unmet 2
• ICD deactivation discussions appropriate in end-stage disease 2

Common Pitfalls to Avoid

During GDMT Optimization 4:

• Delaying initiation of all four medication classes
• Accepting suboptimal doses without attempting uptitration
• Stopping medications for asymptomatic hypotension
• Inadequate monitoring of renal function and electrolytes
• Using non-evidence-based beta-blockers

Clinical Practice Gaps:

• Target doses of all recommended drugs simultaneously achieved in only 1% of eligible patients in real-world registries 4
• Discontinuation rates as high as 55% for ACEis 4
• 66% of clinicians identify hypotension as major barrier despite evidence showing GDMT safe across all baseline BP levels 4

Patient Education:

• Transient dizziness and fatigue are common with dose increases but usually resolve within days 2, 4
• Adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms 4
• Discourage spontaneous discontinuation of GDMT medications without discussion 2