What are the 4 pillars of heart failure therapy, including Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), beta-blockers, diuretics, and other medications like Angiotensin-Receptor Neprilysin Inhibitors (ARNI)?

The 4 Pillars of Heart Failure Therapy

All patients with heart failure and reduced ejection fraction (HFrEF) should receive simultaneous treatment with four foundational medication classes: (1) ACE inhibitors/ARBs/ARNI, (2) beta-blockers, (3) mineralocorticoid receptor antagonists (MRAs), and (4) SGLT2 inhibitors, with diuretics added as needed for fluid management. 1, 2

The Four Pillars Explained

Pillar 1: Renin-Angiotensin System Inhibition

Start with an ACE inhibitor as first-line therapy unless contraindicated. 1, 3

• ACE inhibitors reduce mortality and hospitalization in all patients with current or prior HF symptoms (Class I, Level A evidence) 1
• ARNI (angiotensin receptor-neprilysin inhibitor) should replace ACE inhibitor therapy in ambulatory patients who remain symptomatic despite optimal therapy with ACE inhibitors, beta-blockers, and MRAs (Class I recommendation) 1
• ARNI has the highest probability of reducing all-cause mortality (OR=0.67) and heart failure hospitalization (OR=0.55) compared to all other RAAS blockers 4
• ARBs are recommended only for patients who are ACE inhibitor intolerant, particularly due to cough or angioedema 1, 2
• ACE inhibitors have stronger evidence than ARBs and should be preferred 3, 5

Dosing strategy for ACE inhibitors: 2

• Start low and titrate every 2 weeks to target doses proven in clinical trials
• Enalapril: start 2.5 mg twice daily, target 10-20 mg twice daily
• Lisinopril: start 2.5-5 mg daily, target 30-35 mg daily
• Ramipril: start 2.5 mg daily, target 5 mg twice daily or 10 mg daily

Pillar 2: Beta-Blockers

Only three beta-blockers have proven mortality reduction: bisoprolol, carvedilol, and metoprolol succinate extended-release—benefits cannot be assumed as a class effect. 2, 6

• Beta-blockers are Class I, Level A recommendations for all patients with stable symptomatic HF 1
• Patients must be relatively stable without IV inotropes or marked fluid retention before initiating beta-blockers 2
• Should already be on ACE inhibitor therapy before starting 2

Dosing strategy for beta-blockers: 2

• Carvedilol: start 3.125 mg twice daily, target 25-50 mg twice daily (mean trial dose 37 mg/day)
• Metoprolol succinate ER: start 12.5-25 mg daily, target 200 mg daily (mean trial dose 159 mg/day)
• Bisoprolol: start 1.25 mg daily, target 10 mg daily (mean trial dose 8.6 mg/day)
• Double dose every 1-2 weeks if preceding dose tolerated 2

Pillar 3: Mineralocorticoid Receptor Antagonists (MRAs)

MRAs are recommended for patients who remain symptomatic despite treatment with an ACE inhibitor and beta-blocker (Class I recommendation) 1

• Indicated in NYHA class II-IV heart failure to reduce mortality and morbidity 1, 2
• Also recommended for patients with NYHA class II symptoms who have prior CV hospitalization or elevated natriuretic peptide level 1
• Recommended following acute MI complicated by LVEF <40% with HF symptoms or diabetes 1

Dosing strategy for MRAs: 2

• Spironolactone: start 12.5-25 mg daily, target 25 mg once or twice daily (mean trial dose 26 mg/day)
• Eplerenone: start 25 mg daily, target 50 mg daily (mean trial dose 42.6 mg/day)
• Check potassium and creatinine after 5-7 days, then recheck every 5-7 days until stable 2

Pillar 4: SGLT2 Inhibitors

SGLT2 inhibitors represent the fourth pillar of modern HFrEF therapy, though not explicitly detailed in the older guidelines provided. 7

• Recent evidence supports early simultaneous introduction of all four pillars 7

Diuretics: Essential Adjunctive Therapy (Not a "Pillar")

Diuretics should be added for fluid overload to reduce HF hospitalizations, but are not considered one of the foundational "pillars" because they do not reduce mortality. 1, 3, 2

• Loop diuretics or thiazides always administered in addition to ACE inhibitors 1, 2
• Furosemide: start 20-40 mg, maximum 250-500 mg daily 2
• If inadequate response: increase dose, combine loop diuretic with thiazide, or administer loop diuretic twice daily 1, 2

Implementation Strategy: Simultaneous vs. Sequential

The most recent evidence supports predischarge initiation of all four pillars simultaneously with rapid up-titration within 1 month, rather than the traditional stepwise approach. 7

• Early simultaneous four-pillar strategy significantly reduces HF hospitalization risk during the vulnerable post-discharge phase (p<0.001) 7
• This represents a shift from older guidelines that recommended sequential addition 1

Monitoring Requirements

Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increase, at 3 months, then every 6 months. 3, 2

• Accept creatinine increases up to 50% above baseline or up to 3 mg/dL, whichever is greater 2
• Potassium levels up to 5.5-6.0 mmol/L are acceptable 2
• Avoid potassium-sparing diuretics during ACE inhibitor initiation 1, 2
• Avoid NSAIDs which can worsen renal function 1

Critical Pitfalls to Avoid

Do not underutilize beta-blockers, especially in older adults and those with comorbidities—this is the most common error. 3

• Do not prematurely switch from ACE inhibitors to ARBs without adequate trial of ACE inhibitors 3
• Do not use ARBs as first-line therapy when ACE inhibitors are tolerated 1, 5, 8
• Do not add ARBs to the combination of ACE inhibitor plus beta-blocker (increased adverse effects without clear benefit) 1
• Exercise extreme caution when substituting ARBs in patients with ACE inhibitor-induced angioedema, as angioedema can also occur with ARBs 2