Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction

General Principles of GDMT Titration

• The American College of Cardiology recommends initiating medications at low doses and gradually increasing to target doses shown in clinical trials, with medication adjustments every 1-2 weeks until maximum tolerated or target doses are achieved 1, 2
• The American Heart Association suggests starting medications at low doses and titrating upward to doses shown to reduce cardiovascular events in clinical trials 3
• Medications should be adjusted no more frequently than every 2 weeks to target or maximally tolerated doses, as recommended by the American College of Cardiology 2
• Renal function, potassium, blood pressure, and heart rate should be monitored with each dose adjustment, according to the American Heart Association 3
• The European Society of Cardiology advises assessing for symptoms of hypotension, especially with ACE inhibitors, ARBs, and ARNIs 4
• Asymptomatic or mildly symptomatic low blood pressure should not be a reason for GDMT reduction or cessation, as stated by the European Society of Cardiology 4

Specific Medication Titration Protocols

• The American College of Cardiology recommends the following target doses for ACE inhibitors: lisinopril 20-40 mg daily, enalapril 10-20 mg twice daily, captopril 50 mg three times daily 1
• The American Heart Association suggests the following titration schedule for ACE inhibitors: increase dose every 1-2 weeks as tolerated 3
• The American College of Cardiology recommends the following target doses for ARBs: valsartan 160 mg twice daily, losartan 50-150 mg daily, candesartan 32 mg daily 1
• The American College of Cardiology advises the following initial dosing for ARNI: sacubitril/valsartan 49/51 mg twice daily 1
• The American College of Cardiology recommends the following target dose for ARNI: sacubitril/valsartan 97/103 mg twice daily 1
• The American Heart Association suggests the following titration schedule for beta-blockers: double the dose every 2 weeks as tolerated 2
• The American College of Cardiology recommends the following target doses for beta-blockers: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 1
• The American College of Cardiology advises the following initial dosing for MRAs: spironolactone 12.5-25 mg once daily, eplerenone 25 mg once daily 1
• The American College of Cardiology recommends the following target doses for MRAs: spironolactone 25-50 mg once daily, eplerenone 50 mg once daily 1
• The American College of Cardiology suggests the following initial dosing for SGLT2 inhibitors: dapagliflozin 10 mg once daily, empagliflozin 10 mg once daily 1

Sequencing and Prioritization of GDMT

• The American College of Cardiology recommends initiating beta-blockers and ACEi/ARB/ARNI first, which can be started simultaneously 1, 5
• The American College of Cardiology advises adding MRA for patients with LVEF ≤35% who remain symptomatic despite beta-blockers and ACEi/ARB/ARNI 8
• The American College of Cardiology suggests adding SGLT2 inhibitor regardless of achieving target doses of other medications 5

Special Considerations

• The European Society of Cardiology recommends prioritizing beta-blockers and MRAs in patients with low BP, as they have less effect on BP 4
• The American College of Cardiology advises avoiding MRAs and reducing starting dose of ARNI in patients with eGFR <30 mL/min/1.73m² 5
• The American Heart Association suggests monitoring closely for hyperkalemia, especially when using ACEi/ARBs/ARNIs and MRAs in combination 3