What is the next step in managing a patient with heart failure and reduced ejection fraction who is already on optimal medical therapy including ACE inhibitors or ARBs, beta-blockers, and high-intensity statins?

Next Step in HFrEF Management on Optimal Medical Therapy

Add aldosterone receptor antagonist (spironolactone or eplerenone) if not already prescribed, as this provides substantial mortality benefit with a number needed to treat of 6 over 36 months in patients with HFrEF already on ACE inhibitors and beta-blockers. 1, 2

Mineralocorticoid Receptor Antagonist (MRA) Addition

The most critical next step is ensuring aldosterone blockade is in place. The 2006 AHA/ACC guidelines establish that aldosterone blockade should be used in post-MI patients without significant renal dysfunction or hyperkalemia who are already receiving therapeutic doses of an ACE inhibitor and beta-blocker, have LVEF ≤40%, and have either diabetes or heart failure. 1 This represents a Class I, Level A recommendation that directly addresses your clinical scenario.

Specific Implementation:

• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily if not already prescribed 1, 2
• Uptitrate to target doses (spironolactone 25-50 mg daily, eplerenone 50 mg daily) as tolerated 2
• Monitor potassium and creatinine closely - contraindicated if creatinine >2.5 mg/dL in men or >2.0 mg/dL in women, or potassium >5.0 mEq/L 1

SGLT2 Inhibitor Addition

The second critical addition is an SGLT2 inhibitor (dapagliflozin or empagliflozin), which should be initiated simultaneously with MRA as part of modern quadruple therapy. 2 The ACC now recommends initiating all four medication classes (ACEi/ARB/ARNi, beta-blockers, MRAs, and SGLT2i) simultaneously at low doses as soon as HFrEF is diagnosed, regardless of symptom severity. 2

Key Points:

• SGLT2 inhibitors are now considered foundational therapy alongside ACEi/ARB, beta-blockers, and MRAs 2
• Start at standard doses without requiring diabetes diagnosis 2
• Benefits include reduced hospitalizations and mortality independent of glycemic effects 2

Consider ARNi (Sacubitril/Valsartan) Upgrade

If the patient is on ACE inhibitor or ARB (not ARNi), strongly consider switching to sacubitril/valsartan, which is preferred over ACEi/ARB in NYHA class II-III patients to further reduce morbidity and mortality. 2

Switching Protocol:

• Discontinue ACE inhibitor 36 hours before starting ARNi to avoid angioedema risk 2
• ARBs can be switched immediately to ARNi 2
• Start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily and uptitrate to target 97/103 mg twice daily 2

Hydralazine-Isosorbide Dinitrate for Black Patients

If the patient self-identifies as Black or African American with NYHA class III-IV symptoms, add hydralazine-isosorbide dinitrate combination therapy. 1 This represents a Class I, Level A recommendation specifically for this population already on ACE inhibitors and beta-blockers. 1

Dosing:

• Hydralazine 37.5 mg three times daily initially 1
• Isosorbide dinitrate 20 mg three times daily initially 1
• Titrate to target doses of hydralazine 75 mg and isosorbide dinitrate 40 mg three times daily 1

Device Therapy Consideration

Counsel regarding ICD implantation if LVEF remains ≤35% despite at least 3 months of optimal medical therapy with ACE inhibitor/ARB/ARNi and beta-blocker. 1 This is a Class I recommendation for primary prevention of sudden cardiac death. 1

ICD Counseling Requirements:

• Document discussion of sudden versus non-sudden death risk 1
• Explain ICD efficacy, safety, and risks including potential for inappropriate shocks 1
• Assess for significant comorbidities or limited life expectancy that would preclude benefit 1

Consider cardiac resynchronization therapy (CRT) if QRS duration is prolonged (≥150 ms with LBBB pattern preferred), as this can improve outcomes in HFrEF. 3

Medication Optimization Strategy

The modern approach emphasizes simultaneous initiation of all four foundational medication classes at low doses with sequential uptitration, rather than waiting to achieve target doses before starting the next medication. 2

Uptitration Protocol:

• Start all medications at guideline-recommended low doses (e.g., bisoprolol 1.25 mg, spironolactone 12.5-25 mg) 2
• Uptitrate at 2-week intervals if preceding dose was well tolerated 2
• Continue uptitration even if symptoms improve at lower doses, as clinical trials demonstrated benefits at target doses 2
• Do not delay initiation due to polypharmacy concerns 2

Common Pitfalls to Avoid

• Do not discontinue beta-blockers during acute decompensation unless hemodynamically unstable - they should be continued in most hospitalized HF patients 1
• Do not use non-dihydropyridine calcium channel blockers (diltiazem, verapamil) in HFrEF as they worsen outcomes 4
• Do not fail to uptitrate to target doses used in clinical trials, as beta-blockers alone reduce mortality by 34% at target doses 2
• Do not discontinue medications when LVEF improves - continue guideline-directed medical therapy indefinitely 2

Monitoring Parameters

Assess the following at each uptitration and regularly thereafter: 1

• Fluid status and body weight measured at same time daily 1
• Blood pressure (supine and standing to detect orthostatic hypotension) 1
• Heart rate 1
• Renal function and electrolytes (especially potassium with MRA use) 1, 2
• Symptoms and exercise tolerance 2