What is the treatment for a patient with heart failure, specifically Heart Failure with Reduced Ejection Fraction (HFrEF) or Heart Failure with Preserved Ejection Fraction (HFpEF)?

Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should receive four foundational drug classes—SGLT2 inhibitors, beta-blockers, ARNI (or ACE inhibitor/ARB), and mineralocorticoid receptor antagonists—as these provide meaningful mortality reduction (at least 20% for three of the four classes) and reduce sudden cardiac death. 1

Core Pharmacological Therapy for HFrEF

First-Line Quadruple Therapy

The essential medications for chronic HFrEF include 1:

• SGLT2 inhibitors (dapagliflozin or empagliflozin): Start early as they have minimal blood pressure effects and provide rapid benefit 1
• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol): Proven to prolong life with ≥20% mortality reduction 1
• Neprilysin inhibitor (sacubitril/valsartan 49/51 mg twice daily, titrate to 97/103 mg twice daily): Provides ≥20% mortality reduction and reduces sudden death 1, 2
• Mineralocorticoid receptor antagonists (spironolactone 12.5-25 mg, target 50 mg daily): Provides ≥20% mortality reduction and reduces sudden death 1

Initiation Strategy in Treatment-Naïve Patients

For patients with low blood pressure or concerns about hypotension, start with SGLT2 inhibitors and MRAs first, as these have the least effect on blood pressure but provide rapid beneficial effects. 1

The recommended sequence for low blood pressure patients 1:

1. Step 1: Initiate SGLT2 inhibitor + MRA simultaneously
2. Step 2: Add either low-dose beta-blocker (if heart rate >70 bpm) OR low-dose sacubitril/valsartan 25-50 mg twice daily
3. Step 3: Up-titrate one medication at a time with small increments every 1-2 weeks
4. If sacubitril/valsartan is not tolerated, substitute with low-dose ACE inhibitor (enalapril 2.5 mg twice daily) 1

Alternative Renin-Angiotensin System Blockade

If sacubitril/valsartan is contraindicated or not tolerated 1:

• ACE inhibitors provide modest mortality benefit (5-16% reduction) but do not reduce sudden death
• ARBs are alternatives if ACE inhibitors cause cough or angioedema
• Important: Allow 36-hour washout period when switching from ACE inhibitor to sacubitril/valsartan 2

Adjunctive Therapies

Loop diuretics (furosemide 20-40 mg initial, usual 40-240 mg daily): Use judiciously to control congestion and relieve symptoms 1

Ivabradine: Consider if heart rate remains >70 bpm despite beta-blocker therapy, or as alternative when beta-blockers are not tolerated hemodynamically 1

Hydralazine/isosorbide dinitrate: May prolong survival but potentially inferior to ACE inhibitors; use based on limited modern evidence in select populations 1

Vericiguat: Reduces heart failure hospitalization in high-risk patients with recent decompensation 3

Titration Principles

Up-titrate medications using small increments every 1-2 weeks, one drug at a time, until reaching target or maximum tolerated dose. 1

• Start at low doses and use forced-titration strategy as employed in landmark trials 1
• Monitor blood pressure, heart rate, renal function, and electrolytes every 1-2 days during hospitalization and before discharge 1
• Close follow-up within 1-2 weeks after medication changes 4

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Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF)

SGLT2 inhibitors are the cornerstone of HFpEF therapy, reducing the composite of cardiovascular death and heart failure hospitalization, with empagliflozin (HR 0.79) and dapagliflozin (HR 0.82) showing consistent benefit. 1

Guideline-Directed Medical Therapy for HFpEF

Primary Disease-Modifying Agents

SGLT2 inhibitors 1:

• Dapagliflozin or empagliflozin reduce HF hospitalizations and cardiovascular events
• Effective regardless of diabetes status
• Should be initiated in all patients with HFpEF unless contraindicated

Mineralocorticoid receptor antagonists (spironolactone): Reduce HF hospitalizations (HR 0.83 in TOPCAT) 1

ARNIs (sacubitril/valsartan): Modest reduction in total HF hospitalizations (rate ratio 0.85) in PARAGON-HF, particularly beneficial in patients with lower LVEF ranges within HFpEF spectrum 1

ARBs (candesartan): Reduce investigator-reported HF admissions (CHARM-Preserved) 1

Symptomatic Management

Loop diuretics: Use judiciously as needed to reduce congestion and improve symptoms 1

Beta-blockers: Use only for specific indications including prior myocardial infarction (up to 3 years), angina, or atrial fibrillation; monitor exercise tolerance due to potential chronotropic incompetence 1

Comorbidity Management

Aggressive management of comorbidities is essential 1:

• Hypertension control
• Diabetes management
• Weight loss in obesity
• Atrial fibrillation rate/rhythm control
• Coronary artery disease treatment
• Chronic kidney disease management
• Obstructive sleep apnea treatment

Nonpharmacological Interventions

Exercise training programs: Improve functional capacity and symptoms 1

Weight loss: Beneficial in obese patients with HFpEF 1

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Common Pitfalls and Caveats

Do not reduce or discontinue GDMT for asymptomatic or mildly symptomatic low blood pressure, as this compromises long-term outcomes 1, 4

Do not use thiazide diuretics if eGFR <30 mL/min, except when prescribed synergistically with loop diuretics 1

Avoid concomitant ACE inhibitor use with sacubitril/valsartan due to angioedema risk; ensure 36-hour washout 2

Monitor potassium closely with MRA therapy, especially in patients with renal dysfunction 1

Natriuretic peptides have high sensitivity for HF diagnosis (BNP <100 pg/mL, NT-proBNP <300 pg/mL makes acute HF unlikely), but elevated levels do not automatically confirm HF diagnosis 1

Selective β₁ receptor blockers may be preferred in hypotensive patients due to lesser blood pressure-lowering effect than non-selective beta-blockers 1