What is the approach to using beta blockers in females with normal Ejection Fraction (EF)?

Beta-Blockers in Females with Normal Ejection Fraction

Women with normal ejection fraction should receive lower doses of beta-blockers (approximately 50% of guideline-recommended doses) compared to men, as they experience greater pharmacodynamic effects and higher risk of adverse reactions due to increased drug exposure. 1, 2

Pharmacokinetic Differences in Women

• Women experience 50-100% higher exposure to beta-blockers (particularly CYP2D6-dependent ones like metoprolol, carvedilol, nebivolol, and propranolol) due to:
  • Higher oral bioavailability
  • Lower volume of distribution
  • Slower clearance via CYP2D6 compared to men 1
• This increased exposure persists even after normalization for body weight
• Oral contraceptives can further increase drug exposure 1

Clinical Effects and Dosing Considerations

• Metoprolol produces greater reduction in heart rate and systolic blood pressure during exercise in women than men 1
• Women experience significantly more adverse drug reactions with CYP2D6-dependent beta-blockers 1
• Recent evidence from the BIOSTAT-CHF study showed:
  • Women had approximately 30% lower risk of death or heart failure hospitalization at only 50% of guideline-recommended doses
  • No additional benefit was gained when women were up-titrated to full guideline-recommended doses
  • These findings were confirmed in an independent Asian cohort 1

Recommendations for Beta-Blocker Use in Women with Normal EF

For Women with Heart Failure with Preserved EF (HFpEF):

• Beta-blockers should be used with caution in women with HFpEF (normal EF)
• Evidence suggests potential harm rather than benefit:
  • One study found beta-blocker therapy was associated with higher risk of HF rehospitalization in women with HFpEF (75% vs 18%, p<0.001) 3
  • Recent research indicates beta-blocker use is associated with higher risk of HF hospitalization as EF increases, particularly when EF >60% 4

For Women with Comorbid Conditions:

Beta-blockers remain indicated for women with normal EF who have specific comorbidities:

• Symptomatic angina
• Need for heart rate control
• Post-myocardial infarction
• Atrial fibrillation
• Aortic dissection
• Hyperkinetic circulation with elevated resting heart rate 1

Practical Dosing Algorithm for Women with Normal EF

1. Initial Assessment:

   • Determine if compelling indication exists (angina, post-MI, atrial fibrillation)
   • Measure baseline heart rate, blood pressure, and assess for contraindications

2. Starting Dose:

   • Begin with approximately 50% of the standard starting dose used for men
   • For metoprolol succinate: 6.25-12.5 mg daily (versus standard 12.5-25 mg) 2

3. Titration:

   • Increase dose gradually every 2 weeks if tolerated
   • Target dose should be approximately 50% of the guideline-recommended target dose
   • For metoprolol: target ~100 mg daily (versus standard 200 mg) 1, 2

4. Monitoring:

   • Assess for excessive bradycardia, hypotension, and other adverse effects
   • Monitor for chronotropic incompetence, especially during exercise
   • Consider discontinuation if adverse effects occur or if symptoms worsen

Important Caveats

• Avoid beta-blockers in women with HFpEF without other compelling indications, as they may increase risk of hospitalization 3, 4
• Never abruptly discontinue beta-blockers as this may precipitate worsening heart failure 2
• Women taking oral contraceptives may require even lower doses due to drug interactions 1
• For women of childbearing potential planning pregnancy, beta-blockers may be preferred over ACE inhibitors or ARBs 1

This sex-specific approach acknowledges the pharmacokinetic and pharmacodynamic differences between men and women, potentially improving both efficacy and safety in female patients with normal ejection fraction.