What is the best order to add Guideline-Directed Medical Therapy (GDMT) for Heart Failure with Reduced Ejection Fraction (HFrEF)?

From the Guidelines

The recommended order for initiating guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) is to start with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor-neprilysin inhibitor (ARNI) along with a beta-blocker, followed by a mineralocorticoid receptor antagonist (MRA), and then an SGLT2 inhibitor. This sequence is based on the most recent guidelines, including the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. The guideline recommends starting with low doses of an ACEI, such as lisinopril 2.5-5mg daily or enalapril 2.5mg twice daily, or an ARB like valsartan 40mg twice daily if ACEI is not tolerated, simultaneously with a beta-blocker, such as carvedilol 3.125mg twice daily, metoprolol succinate 12.5-25mg daily, or bisoprolol 1.25mg daily.

After establishing these medications, add spironolactone 12.5-25mg daily or eplerenone 25mg daily as the MRA, and finally, add an SGLT2 inhibitor, such as dapagliflozin 10mg daily or empagliflozin 10mg daily. Titrate each medication to target doses over 2-4 weeks as tolerated, monitoring blood pressure, heart rate, renal function, and potassium levels, as recommended by the guidelines 1. This comprehensive approach has been shown to significantly reduce mortality and hospitalizations in HFrEF patients, and is supported by previous guidelines, including the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 1.

Key points to consider when initiating GDMT for HFrEF include:

• Starting with low doses of ACEI or ARNI and beta-blocker
• Adding MRA after establishing the first two medications
• Finally, adding an SGLT2 inhibitor
• Titration of each medication to target doses over 2-4 weeks as tolerated
• Monitoring of blood pressure, heart rate, renal function, and potassium levels during titration.

This approach targets multiple pathophysiological mechanisms, including the renin-angiotensin-aldosterone system, sympathetic nervous system overactivation, and cardiorenal protection, and has been shown to improve outcomes in HFrEF patients 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Guideline-Directed Medical Therapy (GDMT) for Heart Failure with Reduced Ejection Fraction (HFrEF)

The best order to add GDMT for HFrEF is not explicitly stated in the provided studies. However, the following points can be considered:

• The cornerstone of pharmacological therapy for patients with HFrEF consists of four main drug classes:
  • Renin-angiotensin system inhibitors
  • Evidence-based β-blockers
  • Mineralocorticoid inhibitors
  • Sodium glucose cotransporter 2 inhibitors 2
• The European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) in the treatment of HF with a reduced ejection fraction (HFrEF) 3
• Newer medications targeting combining an ARB with a neprilysin inhibitor (ARNI) sacubitril/valsartan have shown benefits in mortality and can be used in place of an ACE inhibitor or an ARB 3
• Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms 4

Key Considerations

Some key considerations when adding GDMT for HFrEF include:

• The effect of GDMT is most beneficial when medications from the four main drug classes are used in conjunction 2
• Sodium glucose cotransporter 2 (SGLT2) inhibitors can be used in addition to current therapies 3, 5, 4
• Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF 5, 4
• Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology 4

Real-World Experience

Real-world experience with GDMT for HFrEF has shown that:

• Angiotensin receptor neprilysin inhibitor (ARNI) appeared to be safe as regard renal function and effective in real-world practice 6
• Left ventricular reverse remodeling was observed 1 year after heart failure medication treatment, including ARNI 6