What are the recommended initial drugs for a patient with heart failure with mildly reduced ejection fraction (HFrEF) and acute kidney injury (AKI)?

Recommended Drugs for Heart Failure with Mildly Reduced Ejection Fraction and Acute Kidney Injury

In patients with HFmrEF and AKI, initiate SGLT2 inhibitors (dapagliflozin or empagliflozin) as first-line therapy once hemodynamically stable, as these agents reduce HF hospitalizations and cardiovascular mortality while having minimal impact on blood pressure and can be used safely with eGFR ≥20-25 mL/min/1.73 m² 1, 2, 3.

Initial Pharmacologic Approach

First-Line Therapy: SGLT2 Inhibitors

• SGLT2 inhibitors are the safest initial choice in HFmrEF with AKI because they have minimal effects on blood pressure and renal hemodynamics compared to other guideline-directed medical therapies 1.
• Dapagliflozin can be used with eGFR ≥25 mL/min/1.73 m² and empagliflozin with eGFR ≥20 mL/min/1.73 m² 2, 3.
• These agents reduce HF hospitalizations and cardiovascular mortality in HFmrEF with a Class 2a recommendation 1.
• Monitor for osmotic diuresis effects, which may transiently affect renal function 2.

Second-Line Considerations After Stabilization

Beta-Blockers (Class 2b)

• Consider evidence-based beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) once the patient is hemodynamically stable 1.
• Beta-blockers can be initiated cautiously in hospital after acute pulmonary congestion resolves 1.
• Of the three recommended agents, only bisoprolol may accumulate in renal impairment, but titrate to target dose (10 mg daily) or maximally tolerated dose based on clinical response 2.
• These agents have weaker evidence in HFmrEF (Class 2b) particularly for patients with LVEF on the lower end of the 41-49% spectrum 1.

Renin-Angiotensin System Inhibitors (Class 2b)

• ACE inhibitors or ARBs may be considered in HFmrEF patients, particularly those with LVEF closer to 41% 1.
• Critical caveat in AKI context: The presence of AKI requires extreme caution with RAS inhibitors 4, 5, 2.
• If initiating during or immediately after AKI, start at the lowest possible dose and monitor renal function and potassium closely within 1-2 weeks 2.
• Do not use sacubitril/valsartan if eGFR <30 mL/min/1.73 m² 2.
• An initial decline in eGFR of up to 20-30% is acceptable if the patient is clinically stable; this should not prompt discontinuation 3.
• Recent evidence supports early prescription of ACE inhibitors/ARBs in hospitalized AHF patients (even pre-hemodynamic stabilization) without increased adverse events, though this was studied primarily in HFrEF 6.

Mineralocorticoid Receptor Antagonists (Class 2b)

• MRAs may be considered in HFmrEF, particularly with LVEF on the lower end of the spectrum 1.
• In the AKI setting, MRAs require stringent criteria: only use if eGFR ≥30 mL/min/1.73 m² and serum potassium <5.0 mEq/L 1, 2.
• Start with very low doses (6.25-12.5 mg daily or 12.5 mg every other day) in patients with recovering AKI 2.
• Monitor potassium and renal function closely (within 3-7 days of initiation, then regularly) 1, 2.

Essential Supportive Therapy

Diuretics

• Loop diuretics are recommended to manage congestion and improve symptoms 1.
• Adjust doses carefully in AKI to balance decongestion with avoiding further renal injury 1.
• Consider reducing diuretic doses when initiating other GDMT to minimize hypotension risk 1.

Practical Implementation Algorithm

1. Assess hemodynamic stability: Ensure resolution of acute pulmonary congestion and adequate perfusion 1.

2. Check renal function and electrolytes: Document baseline eGFR and potassium before initiating therapy 2.

3. Initiate SGLT2 inhibitor if eGFR ≥20-25 mL/min/1.73 m² (depending on agent) 1, 2.

4. Add beta-blocker once clinically stable, starting at low dose and uptitrating 1.

5. Consider ACE inhibitor/ARB if eGFR recovering and >30 mL/min/1.73 m², starting at lowest dose with close monitoring 1, 2.

6. Consider MRA only if eGFR ≥30 mL/min/1.73 m² and potassium <5.0 mEq/L, using very low starting doses 1, 2.

Critical Pitfalls to Avoid

• Do not withhold SGLT2 inhibitors due to AKI concerns—these are the safest GDMT option in this population and should be prioritized 1, 3.
• Do not permanently discontinue RAS inhibitors for modest eGFR declines (<30% from baseline) if the patient is clinically stable 3.
• Do not use triple RAS blockade (ACEi + ARB + MRA combination) as this increases risk of renal dysfunction and hyperkalemia 1.
• Avoid premature discontinuation of therapies due to laboratory abnormalities alone without clinical deterioration, as discontinuation itself worsens outcomes 1, 4.
• Monitor more frequently in CKD/AKI: Check renal function and potassium within 1-2 weeks of initiating or uptitrating any RAS inhibitor or MRA 2.

Evidence Strength Considerations

The recommendations for HFmrEF are weaker (Class 2b for most agents except SGLT2 inhibitors) compared to HFrEF, as this population was historically underrepresented in clinical trials 1. However, the 2022 AHA/ACC/HFSA guidelines represent the most current evidence, with SGLT2 inhibitors showing the strongest benefit profile 1. The presence of AKI further complicates management, as patients with CKD are systematically undertreated despite evidence supporting therapy continuation in most cases 4, 3.