What guideline‑directed medications should I be prescribed for heart failure with a mid‑range ejection fraction of 42%?

Guideline-Directed Medical Therapy for Heart Failure with Mildly Reduced Ejection Fraction (EF 42%)

You should be prescribed the same four-medication regimen used for heart failure with reduced ejection fraction (HFrEF): an ARNI (sacubitril/valsartan) or ACE inhibitor/ARB, a beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and an SGLT2 inhibitor (dapagliflozin or empagliflozin). 1, 2

Why Your EF of 42% Qualifies for Full HFrEF Treatment

Your ejection fraction of 42% places you in the HFmrEF (heart failure with mildly reduced ejection fraction) category, defined as LVEF 41-49%. 1 However, the 2022 ACC/AHA/HFSA guidelines explicitly recommend treating HFmrEF patients with the same evidence-based therapies as HFrEF patients (LVEF ≤40%). 1 This is because:

• Patients with LVEF in the 41-49% range benefit from similar disease-modifying therapies as those with LVEF ≤40% 3
• The medications below have demonstrated mortality and hospitalization benefits across the spectrum of reduced ejection fraction 2, 4

The Four Foundational Medications You Need

1. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan (ARNI) is strongly preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk 2
• If switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 2
• ACE inhibitors or ARBs reduce mortality by 5-16% if ARNI is not tolerated or available 2

2. Beta-Blocker

• Use carvedilol, metoprolol succinate, or bisoprolol specifically—these are the only beta-blockers proven effective 2
• Provides at least 20% reduction in mortality risk 2
• If you have refractory hypertension, carvedilol is preferred due to its combined α1-β1-β2-blocking properties 2

3. Mineralocorticoid Receptor Antagonist (MRA)

• Spironolactone or eplerenone provide at least 20% reduction in mortality risk 2
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 2
• Requires monitoring of potassium and kidney function 1

4. SGLT2 Inhibitor

• Dapagliflozin or empagliflozin are the newest additions with significant mortality benefits 2
• Unique advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks 2
• Safe in moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 2

The Mortality Benefit You're Missing

Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment. 2 Transitioning from traditional dual therapy (ACE inhibitor and beta-blocker alone) to quadruple therapy can extend life expectancy by approximately 6 years. 2

How These Medications Should Be Started

All four medication classes should be initiated simultaneously at low doses, then uptitrated every 1-2 weeks to target doses. 2, 5 You do not need to wait to achieve target dosing of one medication before starting the next. 2 This simultaneous initiation approach:

• Is supported by the 2022 ACC/AHA/HFSA guidelines 1
• Dramatically improves medication adherence compared to sequential initiation 2
• Currently, less than one-quarter of eligible patients receive all medications concurrently, and only 1% receive target doses of all medications 2

Critical Point About Improved Ejection Fraction

If your ejection fraction improves above 40% with treatment, you must continue all HFrEF medications indefinitely. 1 The guidelines specifically state:

• Patients with previous LVEF ≤40% who improve to >40% are classified as "HFimpEF" (heart failure with improved ejection fraction) 1
• GDMT should be continued to prevent relapse of heart failure and left ventricular dysfunction, even if you become asymptomatic 1
• Discontinuation of medications after EF improvement frequently leads to clinical deterioration 2

Additional Medications for Symptom Relief

• Diuretics (loop diuretics like furosemide) should be used as needed for fluid overload and congestion symptoms 2, 5
• These provide symptom relief but do not reduce mortality 5, 6

Common Pitfalls to Avoid

• Do not stop medications due to asymptomatic low blood pressure. Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 2
• Modest creatinine elevation (up to 30% above baseline) is acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB 2
• Temporary fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue 2
• Avoid non-dihydropyridine calcium channel blockers, moxonidine, and alpha-adrenergic blockers, as they may worsen heart failure 2