When managing heart failure (HF), what guides the decision to add different classes of medications, such as Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), beta-blockers, and Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors?

When to Add the Four Classes of Medications for Heart Failure Management

The four foundational medication classes for heart failure with reduced ejection fraction (HFrEF) should be initiated simultaneously at low doses as soon as HFrEF is diagnosed, regardless of symptom severity, with sequential uptitration to target doses as tolerated. 1

Guideline-Directed Medical Therapy (GDMT) for HFrEF

Initial Approach to Medication Management

• All four medication classes should be started early in the disease course for patients with HFrEF (LVEF ≤40%) 1
• The four medication classes are:
  1. Renin-angiotensin system inhibitors (ACEi/ARB/ARNi)
  2. Beta-blockers
  3. Mineralocorticoid receptor antagonists (MRAs)
  4. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) 1
• Medications may be initiated simultaneously at low doses or sequentially, without waiting to achieve target doses before starting the next medication 1

Medication Initiation and Titration

• Start with low doses as recommended in guidelines (e.g., bisoprolol 1.25mg daily, spironolactone 12.5-25mg daily) 1
• Uptitrate doses at 2-week intervals if the preceding dose was well tolerated 1, 2
• Continue uptitration even if symptoms improve at lower doses, as clinical trials demonstrated benefits at target doses 1
• Monitor heart rate, blood pressure, renal function, and electrolytes during titration 1, 2

Specific Considerations for Each Medication Class

ACEi/ARB/ARNi

• Indicated for all patients with current or previous symptoms of HFrEF 1
• ARNi (sacubitril/valsartan) is preferred over ACEi/ARB in NYHA class II-III patients to further reduce morbidity and mortality 1
• ARBs are recommended when ACEi is not tolerated due to cough or angioedema 1
• Monitor for hypotension, renal dysfunction, and hyperkalemia 1

Beta-Blockers

• One of three evidence-based beta-blockers (bisoprolol, carvedilol, metoprolol succinate) should be used 1
• Initiate even in patients with mild symptoms as they reduce mortality by 34% (the highest relative risk reduction among the four classes) 1
• Start at low doses and double the dose at 2-week intervals if tolerated 1, 2
• Temporary dose reduction may be needed if worsening heart failure occurs during uptitration 2

Mineralocorticoid Receptor Antagonists (MRAs)

• Recommended for patients with NYHA class II-IV symptoms 1
• Provide substantial mortality benefit with NNT of 6 over 36 months 1
• Monitor potassium and renal function, especially in patients with eGFR <60 mL/min/1.73m² 1
• Contraindicated if eGFR <30 mL/min/1.73m² 1

SGLT2 Inhibitors

• Newest addition to GDMT for HFrEF 1
• Dapagliflozin and empagliflozin are approved for HFrEF 1, 3
• Reduce cardiovascular death and heart failure hospitalizations 3
• Can be initiated without regard to glycemic status or presence of diabetes 3

Special Populations and Considerations

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)

• SGLT2i have a Class 2a recommendation 1
• ACEi, ARB, ARNi, MRA, and beta-blockers have weaker (Class 2b) recommendations 1

Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF ≥50%)

• SGLT2i have a Class 2a recommendation 1
• MRAs and ARNi have Class 2b recommendations 1
• Treatment of hypertension is a Class 1 recommendation 1

Improved Ejection Fraction

• Patients with previous HFrEF who now have LVEF >40% should continue their HFrEF treatment 1
• Do not discontinue therapy even if LVEF normalizes 1

Monitoring and Follow-up

• Assess renal function and electrolytes before initiation and periodically thereafter 1
• Monitor for orthostatic hypotension, especially in patients with autonomic dysfunction 2
• Evaluate for clinical improvement in symptoms, exercise tolerance, and quality of life 1
• Adjust diuretic doses based on volume status while maintaining GDMT 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes due to concerns about polypharmacy 1
• Failing to uptitrate to target doses used in clinical trials 1
• Discontinuing medications when LVEF improves 1
• Using calcium channel blockers for HFrEF (Class III: No Benefit) 1
• Treating asymptomatic ventricular arrhythmias without other indications 1

By implementing comprehensive GDMT with all four medication classes early in the disease course, clinicians can significantly improve outcomes, with potential for 2.7-8.3 additional years free from cardiovascular death or heart failure hospitalization 4.