What is the guideline-directed medical therapy (GDMT) for Heart Failure with Reduced Ejection Fraction (HFrEF) with concomitant end-stage Chronic Kidney Disease (CKD)?

Guideline-Directed Medical Therapy for HFrEF with End-Stage CKD

For patients with HFrEF and end-stage CKD, SGLT2 inhibitors are the most strongly recommended therapy with evidence of safety and efficacy extending to CKD stage 4, while other components of GDMT should be used cautiously with close monitoring of renal function and electrolytes. 1, 2

Core Medication Classes for HFrEF with End-Stage CKD

SGLT2 Inhibitors

• SGLT2 inhibitors (dapagliflozin, empagliflozin) have the strongest evidence for safety and efficacy in patients with HFrEF and advanced CKD, with benefits extending to CKD stage 4 (eGFR 15-30 mL/min/1.73m²) 2
• These medications provide cardiovascular benefits through multiple mechanisms including improved decongestion, metabolic shifts toward ketone utilization, and renal protection 1
• SGLT2 inhibitors are recommended as first-line therapy for HFrEF patients with concomitant end-stage CKD 3, 4

Renin-Angiotensin System Inhibitors

• ACE inhibitors, ARBs, or ARNIs have evidence of safety and efficacy up to CKD stage 3B (eGFR ≥30 mL/min/1.73m²) 2
• For CKD stage 4, limited evidence supports the use of ACE inhibitors for reducing cardiovascular death/HF hospitalization 2
• Initial decline in eGFR is expected and should not prompt discontinuation if clinical condition remains stable 2, 5
• Lower starting doses with careful uptitration and close monitoring of renal function and potassium levels are recommended 5

Beta-Blockers

• Evidence-based beta-blockers (carvedilol, metoprolol succinate, bisoprolol) can be used in HFrEF with advanced CKD up to stage 3B 3, 2
• Beta-blockers are generally well-tolerated in advanced CKD as they are not primarily eliminated by the kidneys 5, 6
• Start at lower doses with careful uptitration while monitoring for bradycardia and hypotension 7

Mineralocorticoid Receptor Antagonists (MRAs)

• MRAs (spironolactone, eplerenone) should be used with extreme caution in end-stage CKD due to high risk of hyperkalemia 1, 5
• If used, start at very low doses (12.5 mg spironolactone 2-3 times weekly) with frequent monitoring of potassium levels 6
• Consider avoiding MRAs in patients with eGFR <20 mL/min/1.73m² unless under nephrology co-management 2, 6

Special Considerations

Hydralazine and Isosorbide Dinitrate

• The combination of hydralazine and isosorbide dinitrate may be considered for patients who cannot tolerate RAS inhibitors due to renal insufficiency 1
• This combination is particularly beneficial in self-identified African American patients with HFrEF 1

Diuretic Management

• Loop diuretics should be used for volume management but do not provide mortality benefit 1, 7
• Higher doses or combination diuretic therapy may be needed due to decreased diuretic efficacy in advanced CKD 1
• Close monitoring of volume status, electrolytes, and renal function is essential 7, 5

Device Therapy

• ICD and CRT should still be considered in appropriate candidates with HFrEF and advanced CKD based on standard criteria 1
• The decision for device therapy should consider overall prognosis and comorbidity burden 1

Implementation Strategy

Medication Initiation and Uptitration

• Start with lower doses of all medications compared to those used in patients with normal renal function 5
• Prioritize SGLT2 inhibitors as the first medication to initiate or maintain in patients with HFrEF and end-stage CKD 2, 4
• Uptitrate medications more gradually with more frequent monitoring of renal function and electrolytes 7, 5
• Consider sequential rather than simultaneous initiation of multiple agents 7

Monitoring

• Monitor renal function and electrolytes within 1-2 weeks after initiation or dose changes of RAS inhibitors or MRAs 5
• Assess volume status regularly and adjust diuretic therapy accordingly 1
• A temporary decline in eGFR (up to 30%) after initiation of RAS inhibitors or SGLT2 inhibitors is expected and generally not a reason to discontinue therapy if otherwise stable 2

Common Pitfalls and Caveats

• Underutilization of GDMT in HFrEF patients with advanced CKD is common but leads to worse outcomes 4, 5
• Do not discontinue GDMT based solely on mild-moderate worsening of renal function if the patient is clinically stable 2
• Hyperkalemia risk is highest with combination therapy of ACEi/ARB/ARNI plus MRA in advanced CKD; consider potassium binders if needed 6
• Patients with end-stage CKD have been excluded from most major HFrEF trials, so clinical judgment and close monitoring are essential 2, 6