What is the initial treatment regimen for chronic heart failure with reduced ejection fraction (HFrEF)?

Initial Treatment Regimen for Chronic Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with symptomatic HFrEF should be started immediately on the combination of an ACE inhibitor (or ARNI) plus a beta-blocker, with addition of a mineralocorticoid receptor antagonist (MRA) if symptoms persist, and diuretics as needed for congestion. 1

Foundational Triple Therapy

First-Line: ACE Inhibitor + Beta-Blocker

• Start an ACE inhibitor and beta-blocker simultaneously in all symptomatic HFrEF patients (NYHA Class II-IV) to reduce cardiovascular death and heart failure hospitalization (Class I, Level A recommendation). 1

• Begin with low doses and titrate upward every 2-4 weeks to target maintenance doses proven effective in clinical trials. 1, 2

• ACE inhibitor initiation protocol: 1

  • Review and potentially reduce diuretic dose 24 hours before starting
  • Start with low dose, preferably in the evening when supine to minimize hypotension
  • Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment
  • Avoid NSAIDs and potassium-sparing diuretics during initiation

• Beta-blocker selection: Use evidence-based agents (carvedilol, metoprolol succinate, or bisoprolol) that have demonstrated mortality benefit in HFrEF trials. 1, 3

Second-Line: Add Mineralocorticoid Receptor Antagonist

• Add spironolactone or eplerenone if patients remain symptomatic (NYHA Class II-IV) despite ACE inhibitor and beta-blocker therapy to further reduce hospitalization and death (Class I, Level A). 1

• Monitor serum potassium and creatinine closely—check 5-7 days after initiation and with each dose adjustment until stable. 1

• Contraindicated if baseline potassium >5.0 mEq/L or significant renal dysfunction (eGFR <30 mL/min). 1

Symptomatic Management

Diuretics for Congestion

• Loop diuretics are recommended (not optional) for all patients with signs or symptoms of fluid overload to improve symptoms and exercise capacity (Class I, Level B). 1

• Thiazides can be used if eGFR >30 mL/min, but switch to loop diuretics below this threshold. 1

• For insufficient response: increase loop diuretic dose, administer twice daily, or combine loop diuretic with thiazide for synergistic effect. 1

Advanced Therapy Considerations

ARNI (Sacubitril/Valsartan) as ACE Inhibitor Replacement

• Replace ACE inhibitor with sacubitril/valsartan in ambulatory patients who remain symptomatic despite optimal triple therapy (ACE inhibitor, beta-blocker, MRA) to further reduce cardiovascular death and hospitalization (Class I, Level B). 1

• Mandatory 36-hour washout period required when switching from ACE inhibitor to avoid angioedema risk. 4

• Starting dose is 49/51 mg twice daily, titrate to target dose of 97/103 mg twice daily after 2-4 weeks as tolerated. 4

• The PARADIGM-HF trial demonstrated 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization compared to enalapril (HR 0.80,95% CI 0.73-0.87, p<0.0001). 4

Emerging Therapies

• SGLT2 inhibitors (dapagliflozin, empagliflozin) represent a major recent advancement, significantly reducing cardiovascular and all-cause mortality regardless of diabetes status. 5, 3

• Network meta-analysis identified ARNI + beta-blocker + MRA and SGLT2i + ACE inhibitor + beta-blocker + MRA as the most effective combinations for reducing hospitalization and mortality. 5

Critical Pitfalls to Avoid

Contraindicated Combinations

• Never combine ACE inhibitor with ARB and MRA due to increased risk of renal dysfunction and life-threatening hyperkalemia (Class III, Level C). 1

• Avoid diltiazem and verapamil in HFrEF as they worsen heart failure and increase hospitalization risk (Class III, Level C). 1

Monitoring Requirements

• Check blood pressure, renal function (creatinine/eGFR), and electrolytes (particularly potassium) at baseline, 1-2 weeks after each medication adjustment, at 3 months, then every 6 months. 1

• Avoid excessive diuresis before initiating ACE inhibitors, as volume depletion increases hypotension and acute kidney injury risk. 1

Device Therapy Timing

• Implantable cardioverter-defibrillator (ICD) is indicated for primary prevention in patients with LVEF ≤35% despite ≥3 months of optimal medical therapy, NYHA Class II-III, and expected survival >1 year (Class I, Level A for ischemic cardiomyopathy, Level B for dilated cardiomyopathy). 1

• Do not implant ICD within 40 days of myocardial infarction as it does not improve prognosis during this period (Class III, Level A). 1

• Cardiac resynchronization therapy (CRT) is recommended for patients in sinus rhythm with QRS ≥150 msec, LBBB morphology, and LVEF ≤35% despite optimal medical therapy (Class I, Level A). 1

Implementation Reality

• Recent registry data show that while 89-93% of HFrEF patients receive ACE inhibitors/ARBs and 91-92% receive beta-blockers, only 35-46% receive MRAs and 19-30% receive SGLT2 inhibitors, indicating substantial treatment gaps. 6

• De-escalation of guideline-directed therapy during hospitalization (particularly for non-cardiovascular causes) is common and associated with worse post-discharge survival—robust plans for medication re-escalation must be included in discharge planning. 7