What are the risks, benefits, and side effects of Guideline-Directed Medical Therapy (GDMT) for patients with Heart Failure with Reduced Ejection Fraction (HFrEF)?

From the Guidelines

Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) should be initiated and uptitrated to reduce mortality and hospitalizations, despite potential side effects, as the benefits significantly outweigh the risks when patients are appropriately selected and monitored. The four cornerstone medication classes for HFrEF include angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors.

• ACEIs, such as lisinopril (10-40 mg daily) or enalapril (5-20 mg twice daily), block the renin-angiotensin system to reduce afterload and cardiac remodeling, but may cause cough, angioedema, hyperkalemia, or worsening renal function 1.
• ARNIs, like sacubitril/valsartan (24/26 mg to 97/103 mg twice daily), are superior to ACEIs but can cause similar side effects plus hypotension 1.
• Beta-blockers, such as carvedilol (3.125-25 mg twice daily) or metoprolol succinate (12.5-200 mg daily), reduce sympathetic stimulation and improve cardiac remodeling, but may cause fatigue, bradycardia, or bronchospasm 1.
• MRAs, like spironolactone (12.5-50 mg daily) or eplerenone (25-50 mg daily), block aldosterone to reduce fibrosis and sodium retention, but risk hyperkalemia and gynecomastia 1.
• SGLT2 inhibitors, such as dapagliflozin (10 mg daily) or empagliflozin (10 mg daily), provide cardiorenal protection through multiple mechanisms, but may cause genital infections or volume depletion 1. The overall burden of adverse events (AEs) in patients with HFrEF is high, but most AEs cannot be clearly attributed to GDMT, and the benefits of reduced mortality and hospitalizations outweigh the risks 1.
• AEs, such as hypotension, occur at non-trivial rates among patients receiving placebo in trials, and are less likely to occur with prompt initiation and titration of GDMT 1.
• The addition of single GDMT drug resulted in between 0.8% fewer to 5% more patients experiencing any AE at all, a difference which was often not statistically significant 1.
• The absolute difference rates for most individual AEs were less than 5% between intervention and placebo, and in some cases, AEs occurred less often with intervention 1. Therefore, clinicians should be thoughtful about whether symptoms should prompt a change in GDMT, and whether drugs, once stopped, should be re-trialed, especially given concerns that stopping GDMT may in fact worsen symptoms 1.

From the FDA Drug Label

Sacubitril and valsartan tablets are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan In PARADIGM-HF, sacubitril and valsartan decreased plasma NT- proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

The benefits of Guideline-Directed Medical Therapy (GDMT) with sacubitril and valsartan for patients with Heart Failure with Reduced Ejection Fraction (HFrEF) include:

• Reduced risk of cardiovascular death
• Reduced risk of hospitalization for heart failure
• Improved cardiovascular outcomes
• Decreased plasma NT-proBNP levels
• Increased plasma BNP levels
• Increased urine cGMP levels

The risks of GDMT with sacubitril and valsartan for patients with HFrEF include:

• Hypotension
• Fetal toxicity (when used during pregnancy)
• Potential increase in CSF Aβ1-38 levels (unknown clinical relevance)

The side effects of GDMT with sacubitril and valsartan for patients with HFrEF may include:

• Hypotension
• Increased risk of angioedema (when used with ACE inhibitors)
• Potential changes in blood pressure when co-administered with other medications (e.g. sildenafil, nitroglycerin) 2, 2, 2

From the Research

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

• The use of GDMT in patients with HFrEF can be limited by intolerance or fear of potential complications, such as symptomatic hypotension, atrial fibrillation, kidney disease, or worsening renal function, and hyperkalemia 3
• Concomitant use of all four drug groups in target doses can be challenging in clinical practice, and may lead to unnecessary reduction or cessation of life-saving treatment 3
• Increasing age, higher ejection fraction, atrial fibrillation/flutter, chronic obstructive pulmonary disease (COPD), prior stroke, and dementia are associated with decreased odds of GDMT use 4

Benefits of GDMT for Patients with HFrEF

• GDMT is the cornerstone of pharmacological therapy for patients with HFrEF, and consists of four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors, and sodium glucose cotransporter 2 inhibitors 5
• The use of GDMT has been shown to improve clinical outcomes in patients with HFrEF, and is recommended for all patients with this condition 5, 4
• The effect of GDMT is most beneficial when medications from the four main drug classes are used in conjunction 5

Side Effects of GDMT for Patients with HFrEF

• The side effects of GDMT can include symptomatic hypotension, atrial fibrillation, kidney disease, or worsening renal function, and hyperkalemia 3
• The use of certain medications, such as vasodilators, may be limited to specific populations, such as Black patients 4
• The use of GDMT can be associated with a range of comorbidities, including chronic obstructive pulmonary disease (COPD), prior stroke, and dementia 4

Implementation of GDMT in Clinical Practice

• Despite the benefits of GDMT, there is an underutilization of this therapy in clinical practice, partially due to lack of awareness of how to safely and effectively initiate and titrate these medications 5
• Strategies to improve guideline-directed use of HFrEF therapies are urgently needed, particularly in the early time periods following diagnosis 6
• The use of GDMT can be influenced by a range of factors, including patient characteristics, comorbidities, and healthcare system factors 4, 6