What are the four pillars of heart failure medications for adults with heart failure with reduced ejection fraction?

Four Pillars of Heart Failure Medications for HFrEF

All adults with heart failure with reduced ejection fraction (HFrEF) should receive simultaneous treatment with four foundational drug classes: (1) beta-blockers, (2) ACE inhibitors/ARBs/ARNI, (3) mineralocorticoid receptor antagonists (MRAs), and (4) SGLT2 inhibitors. 1

The Four Pillars

1. Beta-Blockers

• Use only evidence-based agents: bisoprolol, carvedilol, or sustained-release metoprolol succinate 1
• These agents reduce cardiovascular death and heart failure hospitalization 1
• Start simultaneously with ACE inhibitor/ARB/ARNI, not sequentially 2
• Begin with low doses and titrate every 2-4 weeks to target maintenance doses proven in clinical trials 2

2. Renin-Angiotensin System Inhibitors

• First-line options (in order of preference):

  • ARNI (sacubitril/valsartan) is preferred over ACE inhibitors in ambulatory patients with symptomatic HFrEF to further reduce cardiovascular death and hospitalization 2
  • ACE inhibitors (enalapril, lisinopril, ramipril) if ARNI not available 1
  • ARBs (candesartan, valsartan) only if ACE inhibitor intolerant due to cough or angioedema 1, 3

• Critical initiation protocol for ACE inhibitors: 2

  • Review and potentially reduce diuretic dose 24 hours before starting
  • Start with low dose
  • Monitor blood pressure, renal function, and electrolytes
  • Avoid NSAIDs and potassium-sparing diuretics during initiation

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone or eplerenone in all eligible patients with HFrEF 1
• Eligibility criteria: 3
  • Serum creatinine ≤2.5 mg/dL in men, ≤2.0 mg/dL in women
  • Serum potassium <5.0 mEq/L
  • eGFR >30 mL/min
• Requires careful monitoring for renal function and potassium 3

4. SGLT2 Inhibitors

• All patients with HFrEF should receive SGLT2 inhibitors regardless of diabetes status 1
• These agents significantly reduce cardiovascular and all-cause mortality 4
• Should be initiated as part of foundational therapy, not as add-on 5, 6

Initiation Strategy

Simultaneous initiation of all four pillars is superior to stepwise approach: 6

• Start all four drug classes together, ideally before hospital discharge for admitted patients 6
• Rapid up-titration within 1 month reduces heart failure hospitalization risk during the vulnerable post-discharge phase 6
• This approach contradicts older sequential strategies and represents current best practice 5, 6

Additional Therapies (Beyond the Four Pillars)

Loop Diuretics

• Required for all patients with signs or symptoms of fluid overload 1, 2
• Not considered a "pillar" because they provide symptomatic relief without mortality benefit 1
• Avoid excessive diuresis before initiating ACE inhibitors, as volume depletion increases hypotension and acute kidney injury risk 2

Ivabradine (Fifth-Line Agent)

• Indicated only for: patients in sinus rhythm with resting heart rate ≥70 bpm despite maximally tolerated beta-blocker doses (or beta-blocker contraindication) 7
• Reduces hospitalization risk but does not reduce mortality 4
• Starting dose: 5 mg twice daily with food, titrate to maximum 7.5 mg twice daily based on heart rate 7

Hydralazine/Isosorbide Dinitrate

• Reserved for patients intolerant to both ACE inhibitors and ARBs 1, 3
• Particularly beneficial in self-described African American patients with class II-IV HF 1, 3

Monitoring Requirements

Check at each medication adjustment: 2

• Blood pressure
• Renal function (creatinine, eGFR)
• Electrolytes (especially potassium)

Monitoring schedule: 2

• Baseline before initiation
• 1-2 weeks after each dose adjustment
• At 3 months
• Every 6 months thereafter

Critical Contraindications and Pitfalls

Dangerous Drug Combinations

• Never combine ACE inhibitor + ARB + MRA due to life-threatening hyperkalemia and renal dysfunction risk 2
• Avoid diltiazem and verapamil in HFrEF—they worsen heart failure and increase hospitalization 2

Beta-Blocker Cautions

• Ivabradine increases atrial fibrillation risk (5.0% vs 3.9% with placebo); regularly monitor cardiac rhythm and discontinue if atrial fibrillation develops 7
• Ivabradine causes bradycardia (6.0% per patient-year); monitor heart rate and adjust dose accordingly 7

Device Therapy Timing

• ICD for primary prevention: LVEF ≤35% after ≥3 months of optimal medical therapy, NYHA class II-III, expected survival >1 year 2
• Do not implant ICD within 40 days of myocardial infarction—no prognostic benefit during this period 2
• CRT: indicated for sinus rhythm with QRS ≥150 msec, LBBB morphology, LVEF ≤35% despite optimal medical therapy 2