Best Pharmacological Approach for Ejection Fraction of 40%
For a patient with an ejection fraction of 40%, the best initial pharmacological approach is to start an ACE inhibitor or ARB, along with a beta-blocker, as these medications form the cornerstone of therapy for reduced ejection fraction and have demonstrated mortality benefit. 1
First-Line Medications
ACE Inhibitors/ARBs
- ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction < 40% unless contraindicated 1
- ARBs are recommended as an alternative in patients who are ACE inhibitor intolerant 1
- These medications should be initiated as soon as the patient is hemodynamically stable 1
Beta-Blockers
- Beta-blocker therapy should be used in all patients with left ventricular systolic dysfunction (ejection fraction ≤40%) with heart failure or prior myocardial infarction 1
- Use should be limited to evidence-based beta-blockers that have shown mortality benefit: carvedilol, metoprolol succinate, or bisoprolol 1, 2
- Beta-blockers should be started at low doses and gradually uptitrated as tolerated 2
Second-Line Medications
Mineralocorticoid Receptor Antagonists (MRAs)
- Aldosterone blockade is recommended in patients with ejection fraction < 40% who also have heart failure or diabetes 1
- Options include spironolactone or eplerenone 2
- Close monitoring of renal function and potassium levels is essential when using these agents 2, 3
SGLT2 Inhibitors
- Recent evidence supports the addition of SGLT2 inhibitors to the treatment regimen, as they have demonstrated significant reduction in the composite of cardiovascular death or heart failure hospitalizations 4
- SGLT2 inhibitors reduced the risk of heart failure hospitalizations by 26% in patients with mildly reduced ejection fraction 4
Advanced Therapy Options
Sacubitril/Valsartan (ARNI)
- Consider replacing ACE inhibitor/ARB with sacubitril/valsartan in patients who remain symptomatic despite optimal treatment with an ACE inhibitor/ARB, beta-blocker, and MRA 1, 5
- Sacubitril/valsartan works by inhibiting neprilysin via LBQ657 (active metabolite of sacubitril) and blocking angiotensin II type-1 receptor via valsartan 5
- ARNi reduced the risk of heart failure hospitalizations by 40% in patients with mildly reduced ejection fraction 4
Medications to Avoid
- Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) should be avoided due to their negative inotropic effects and risk of worsening heart failure 2, 3
- NSAIDs and COX-2 inhibitors should be avoided as they cause sodium and water retention 3
- Class I antiarrhythmic agents should be avoided due to potential to worsen heart failure 3
Practical Implementation Strategy
- Initial Visit: Start with low doses of both an ACE inhibitor (or ARB) and a beta-blocker simultaneously 6
- 1-2 Weeks Later: Consider adding or switching to sacubitril/valsartan if appropriate 6
- 2-4 Weeks Later: Add an MRA if the patient has adequate renal function and normal potassium levels 6
- Follow-up Visit: Consider adding an SGLT2 inhibitor to the regimen 7, 6
Monitoring Recommendations
- Monitor renal function and electrolytes closely, particularly when initiating or uptitrating ACE inhibitors/ARBs and MRAs 2, 3
- Watch for symptomatic hypotension, especially when combining multiple agents that lower blood pressure 2
- Assess for signs of worsening heart failure during initiation and uptitration of medications 2
Special Considerations
- An ejection fraction of 40% falls at the borderline between heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF) 3
- Evidence suggests that patients with mildly reduced ejection fraction benefit from similar pharmacological approaches as those with more severely reduced ejection fraction 4, 8
- Rapid initiation of all four foundational drug classes (ACE inhibitor/ARB/ARNI, beta-blocker, MRA, SGLT2 inhibitor) within 2-4 weeks may provide better outcomes than the traditional sequential approach 6