What is the guideline‑directed medical therapy for an adult with heart failure with reduced ejection fraction and a left‑ventricular ejection fraction of 43%?

Treatment of Heart Failure with Ejection Fraction 43%

A patient with LVEF 43% has heart failure with mildly reduced ejection fraction (HFmrEF) and should receive the identical four-pillar guideline-directed medical therapy used for HFrEF—specifically, simultaneous initiation of an ARNI (or ACE-inhibitor), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—because this EF category follows a dynamic trajectory and shares the same therapeutic responsiveness as HFrEF. 1, 2

Classification and Rationale

• LVEF 43% falls into the HFmrEF category (LVEF 41–49%), which the 2022 ACC/AHA guidelines explicitly state warrants the same therapeutic approach as HFrEF (LVEF ≤40%). 1

• HFmrEF represents a dynamic state—approximately 27% of patients decline to HFrEF (LVEF ≤40%) while 45% improve to HFpEF (LVEF ≥50%) over time, making serial LVEF monitoring essential every 6–12 months. 2, 3

• Post-hoc analyses and subgroup data demonstrate that medications proven effective in HFrEF also reduce cardiovascular mortality and HF hospitalization in the mildly reduced EF range. 2, 3

Four-Pillar Pharmacologic Therapy (Initiate All Simultaneously)

1. Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

• Start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily as first-line RAAS inhibition; post-hoc analyses show superior reduction in HF hospitalization and mortality even in the mildly reduced EF range compared with ACE-inhibitors. 2, 4

• Titrate to the target dose of 97/103 mg twice daily over 3–6 weeks while monitoring blood pressure, renal function, and potassium. 2, 4

• If ARNI is unavailable or unaffordable, substitute an ACE-inhibitor (enalapril 10–20 mg twice daily or lisinopril 20–40 mg once daily) and titrate to at least 50% of the evidence-based target dose. 2

• ARBs are reserved only for patients who develop intolerable cough with ACE-inhibitors, as the evidence base for mortality reduction is stronger for ACE-inhibitors and ARNIs. 2

2. Beta-Blocker

• Initiate a guideline-recommended beta-blocker (carvedilol 3.125 mg twice daily, metoprolol succinate 12.5–25 mg daily, or bisoprolol 1.25 mg daily) concurrently with ARNI; beta-blockers confer mortality benefit in all patients with LVEF <50% regardless of symptom status. 2, 4

• Titrate every 1–2 weeks toward target doses: carvedilol 25–50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily, aiming for a resting heart rate of 50–60 bpm. 2, 4

• Use a "start-low, go-slow" approach while monitoring heart rate, blood pressure, and clinical status after each dose increase. 2

3. Mineralocorticoid Receptor Antagonist (MRA)

• Add spironolactone 12.5–25 mg daily (or eplerenone 25 mg daily) for patients with LVEF ≤35% after initial therapy, provided eGFR ≥30 mL/min/1.73 m² and serum potassium ≤5.0 mmol/L. 2, 4

• For LVEF 41–49%, MRA initiation is reasonable (Class IIa) if the patient has persistent NYHA class II–IV symptoms despite ARNI and beta-blocker therapy. 2

• Check potassium and creatinine at 3 days, 1 week, then monthly for three months to detect hyperkalemia; contraindicated if eGFR <30 mL/min/1.73 m² or K⁺ >5.0 mmol/L. 2, 4

4. SGLT2 Inhibitor

• Prescribe dapagliflozin 10 mg daily or empagliflozin 10 mg daily irrespective of diabetes status; this class reduces cardiovascular mortality, all-cause mortality, and HF hospitalization across the full spectrum of reduced and mildly reduced EF. 2, 4

• SGLT2 inhibitors carry a Class I, Level A recommendation and should be started at full dose immediately with minimal blood-pressure effects. 2, 4

Monitoring Strategy

• 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, LVEF >40%) or progression to HFrEF (LVEF ≤40%). 2, 5

• Continue full GDMT even if LVEF improves above 40% (HFimpEF); abrupt discontinuation is associated with relapse of LV dysfunction and clinical HF (ACC/AHA Class I, Level A). 2, 4

• Measure natriuretic peptides (BNP or NT-proBNP) to support the diagnosis and provide prognostic information, recognizing that normal levels do not rule out HFmrEF. 2, 5

Device Therapy Considerations

• Implantable cardioverter-defibrillator (ICD) is not routinely indicated in patients with LVEF 41–49% because primary-prevention trials enrolled patients with LVEF ≤35% (ACC/AHA Class III, Harm). 2

• Re-evaluate LVEF after 3–6 months of optimal medical therapy; if EF declines to ≤35% and the patient meets standard ICD criteria (≥40 days post-MI for ischemic disease or non-ischemic cardiomyopathy with expected survival >1 year), primary-prevention ICD becomes indicated. 2

• Cardiac resynchronization therapy (CRT) is not indicated unless LVEF falls to ≤35% together with left-bundle-branch block (QRS ≥150 ms) and sinus rhythm. 2

Additional Pharmacologic Considerations

• Loop diuretics (furosemide, torsemide, or bumetanide) should be used to relieve congestion, titrating to the lowest dose that maintains euvolemia; diuretics do not confer mortality benefit. 4, 5

• Ivabradine (starting at 2.5–5 mg twice daily) should be considered for patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker therapy. 4

• Hydralazine/isosorbide dinitrate combination provides additional benefit in self-identified African-American patients with NYHA class III–IV symptoms despite optimal therapy. 4

Critical Pitfalls to Avoid

• Do not postpone GDMT awaiting symptom development; early treatment in asymptomatic or mildly symptomatic LV dysfunction reduces mortality and prevents progression to overt HF (ACC/AHA Class I, Level A). 2

• Avoid reliance on a single LVEF measurement for definitive therapeutic decisions; confirm with repeat imaging to prevent misclassification due to measurement variability. 2, 5

• Never discontinue GDMT when LVEF improves above 40%; maintain therapy to prevent relapse of ventricular dysfunction and clinical HF. 2, 4

• Do not combine ACE-inhibitors with ARBs or with sacubitril/valsartan, because dual RAAS blockade increases adverse events without additional benefit (ACC/AHA Class III, Harm). 4

Up-Titration Algorithm

• Increase one medication at a time every 1–2 weeks, selecting the class most likely to be tolerated based on hemodynamics. 4

• If heart rate >70 bpm, prioritize beta-blocker up-titration to target doses. 4

• If systolic blood pressure >100 mmHg, up-titrate ARNI/ACE-inhibitor toward target doses. 4

• If serum potassium <4.5 mmol/L and renal function is stable, up-titrate MRA toward target doses. 4

• Before each dose increase, re-measure blood pressure and heart rate; after each MRA or ARNI/ACE-inhibitor increase, re-check potassium and creatinine 1–2 weeks later. 4