What are the causes of a declining Left Ventricular Ejection Fraction (LVEF) in heart failure over a six-month period?

From the Guidelines

Worsening heart failure with reduced ejection fraction (EF) over a six-month period is often caused by a combination of factors, including medication non-adherence, progression of underlying cardiac disease, and comorbid conditions, as highlighted in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. The causes of worsening heart failure EF can be multifaceted and may involve:

• Uncontrolled hypertension
• Medication non-adherence, particularly to guideline-directed medical therapy (GDMT)
• Dietary indiscretion with excessive sodium intake
• Progression of coronary artery disease
• Development of arrhythmias, such as atrial fibrillation
• Worsening valve disease
• Undiagnosed sleep apnea
• Thyroid dysfunction
• Anemia
• Kidney disease progression
• Medication side effects, including those from non-steroidal anti-inflammatory drugs (NSAIDs), certain diabetes medications, and some cancer treatments
• Acute infections or inflammatory conditions According to the 2022 AHA/ACC/HFSA guideline, the trajectory of LVEF over time is important to evaluate, and a significant reduction in LVEF over time is a poor prognostic factor 1. Therefore, management of worsening heart failure EF should focus on optimizing GDMT, addressing underlying causes, and implementing lifestyle modifications, such as sodium restriction, fluid restriction if needed, regular physical activity, and weight monitoring, as well as regular follow-up appointments with comprehensive assessment to prevent further deterioration of cardiac function 1.

From the FDA Drug Label

The underlying cause of CHF was coronary artery disease in 68% of patients. The main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decompensation (9%), and bradycardia (6%). Most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses The main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decompensation (9%), and bradycardia (6%).

The causes of worsening heart failure EF over half a year are not directly stated in the label. However, the label mentions that coronary artery disease was the underlying cause of CHF in 68% of patients.

• Hypotension
• Fatigue
• Dyspnea
• Dizziness
• History of cardiac decompensation
• Bradycardia are mentioned as reasons for not receiving target beta-blocker doses, but it is unclear if these are direct causes of worsening heart failure EF. 2

From the Research

Causes of Worsening Heart Failure EF

• A worsening heart failure event is associated with a higher risk of death and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) 3, 4.
• Patients with HFrEF and a recent worsening heart failure event have a lower ejection fraction, a greater burden of comorbidities, and more echocardiographic evidence of cardiac dysfunction compared to those without a recent worsening heart failure event 4.
• The use of angiotensin-converting-enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) can affect outcomes in patients with HFrEF, with ACE-Is being the first-line option 5, 6.
• Combination therapy with ACE-Is and ARBs may not provide additional benefits and may potentially be harmful 5.
• Comorbidities, such as diabetes and hypertension, can also contribute to worsening heart failure EF 7, 4.
• Diastolic dysfunction is apparent in all patients with heart failure, regardless of ejection fraction, and can contribute to worsening heart failure EF 7.

Factors Influencing Worsening Heart Failure EF

• Severity of left ventricular dysfunction, with patients having an LVEF ≤25% being at higher risk of death and hospitalization compared to those with LVEF 26% to 35% 3.
• Use of guideline-directed therapies, such as beta-blockers and mineralocorticoid receptor antagonists, can influence outcomes in patients with HFrEF 3, 4.
• Racial and ethnic disparities, with under-represented groups being more likely to experience worsening heart failure EF 4.

Potential Therapeutic Targets

• Increasing c-GMP may be a potential therapeutic target in heart failure with preserved ejection fraction (HFpEF) 7.
• Novel therapies are needed to address the high rates of death and hospitalization in patients with HFrEF and recent worsening heart failure events 4.