What is the first‑line pharmacologic regimen for an adult with heart failure and a left‑ventricular ejection fraction of 40‑45% (HFmrEF)?

First-Line Treatment for Heart Failure with EF 40-45%

Patients with heart failure and ejection fraction of 40-45% (HFmrEF) should be treated with the same four-pillar guideline-directed medical therapy as HFrEF: an ARNI (sacubitril/valsartan preferred over ACE inhibitor/ARB), evidence-based beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor, initiated rapidly and titrated to target doses. 1, 2

Understanding the EF 40-45% Category

• An ejection fraction of 40-45% is classified as heart failure with mildly reduced ejection fraction (HFmrEF), which follows a dynamic trajectory and warrants the same therapeutic approach as HFrEF. 1, 2
• This EF range is NOT preserved ejection fraction—approximately 27% of HFmrEF patients decline to LVEF ≤40%, while 45% improve to LVEF ≥50%, making aggressive early treatment critical. 2
• The threshold for considering RAAS inhibitor therapy is an EF <50% because of the preservation of cavity size in patients with advanced systolic failure. 1

The Four-Pillar Pharmacologic Regimen

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Initiate sacubitril/valsartan as first-line therapy rather than ACE inhibitor or ARB—post-hoc analyses demonstrate superior reduction in HF hospitalization and mortality even in the mildly reduced EF range. 2
• If ACE inhibitor is used instead, start at low doses and titrate upward to doses proven in clinical trials (e.g., enalapril 10-20 mg twice daily, lisinopril 20-40 mg daily). 3
• ARBs are an alternative only if ACE inhibitors or ARNI are not tolerated due to intolerable adverse effects, as the evidence base is stronger for ACE inhibitors. 3
• Target at least 50% of the evidence-based target dose for these medications. 3

2. Evidence-Based Beta-Blockers

• Prescribe one of three beta-blockers proven to reduce mortality: bisoprolol, carvedilol, or metoprolol succinate (sustained-release) for all patients with current or prior symptoms and LVEF <50%. 3, 1, 2
• Beta-blockers should be initiated concurrently with ARNI, as they confer mortality benefit in all patients with LVEF <50% regardless of symptom status. 2
• Use a "start-low, go-slow" approach with gradual incremental dose increases if lower doses are well tolerated, reviewing heart rate, blood pressure, and clinical status after each titration. 3
• Make every effort to achieve target doses shown effective in major clinical trials (e.g., carvedilol 25 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily). 3

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Add spironolactone or eplerenone for patients with persisting symptoms (NYHA Class II-IV) and LVEF <50% despite treatment with ARNI/ACE inhibitor and beta-blocker, to reduce HF hospitalization and premature death. 1
• MRAs are contraindicated if eGFR <30 mL/min/1.73 m² or serum potassium >5.0 mmol/L, requiring close monitoring of renal function and potassium levels. 2
• MRAs specifically reduce sudden cardiac death in addition to all-cause mortality. 3

4. SGLT2 Inhibitors

• Prescribe dapagliflozin or empagliflozin irrespective of diabetes status, as this class reduces cardiovascular mortality, all-cause mortality, and HF hospitalization across the full spectrum of reduced and mildly reduced EF. 1, 2
• SGLT2 inhibitors are highly effective, well-tolerated, easy to use, and have Class I, Level A guideline recommendation—they consistently demonstrate substantial relative and absolute risk reductions. 3
• This is the newest pillar of therapy and should not be omitted despite being the most recent addition. 4, 5

Practical Implementation Strategy

Rapid Sequential Initiation

• Initiate all four medication classes as early as possible to establish effective therapy, even at low doses—this is preferable to starting fewer medications at maximum dose. 6, 7
• The goal is to introduce all four drug classes within 4-6 weeks, followed by an 8-week dose up-titration period. 7
• Adjust therapies no more frequently than every 2 weeks to target doses or maximally tolerated doses. 3
• Most patients should achieve optimal treatment protocol within 2 months, which should be the treatment goal. 6

Monitoring Requirements

• Schedule clinical follow-up every 3-6 months initially to assess symptom emergence, medication tolerance, blood pressure, renal function, and serum potassium. 2
• Repeat transthoracic echocardiography every 6-12 months to track LVEF trajectory and identify either improvement (HFimpEF) or progression to HFrEF. 2
• Monitor renal function regularly when taking ACE inhibitors/ARNI, particularly when dose is increased or when other medications affecting renal function are added. 8

Critical Pitfalls to Avoid

• Do NOT postpone GDMT awaiting symptom development—early treatment in asymptomatic LV dysfunction reduces mortality and prevents progression to overt HF. 2
• Do NOT rely on a single LVEF measurement for definitive therapeutic decisions; obtain two consecutive LVEF measurements to avoid misclassification due to measurement variability. 2
• Do NOT discontinue GDMT if LVEF improves above 40% (HFimpEF)—abrupt discontinuation is associated with relapse of LV dysfunction and clinical HF. 1, 2
• Avoid calcium channel blockers (verapamil, diltiazem, short-acting dihydropyridines), Class I antiarrhythmics, NSAIDs, and COX-2 inhibitors, as they worsen heart failure outcomes. 8

Additional Considerations

• Diuretics should be added as needed for fluid retention, but they do not reduce mortality or sudden death. 3
• Device therapy (ICD, CRT) is not routinely indicated in patients with LVEF 41-49% unless EF declines to ≤35% after 3-6 months of optimal medical therapy. 2
• Aggressive treatment of hypertension and hyperlipidemia is especially important in those with prior ischemic events. 2