The following are key points to remember from this state-of-the-art review about medical management of heart failure with reduced ejection fraction (HFrEF) in patients with advanced renal disease:

1. Many pivotal clinical trials for guideline-directed HFrEF therapies excluded patients with severe kidney disease, resulting in limited evidence for contemporary guideline-directed medical therapy (GDMT) in those with advanced chronic kidney disease (CKD) and HFrEF. Lack of universal outcome definitions in cardio-renal disease is also a key limitation.
2. Although the use of serum creatinine (sCr) is a common clinical approach, sCr alone is an imperfect measurement of kidney function, influenced by characteristics such as age, gender, race, and muscle mass. Also, in the absence of evidence of kidney damage, mild decreases in estimated glomerular filtration rate (eGFR) do not fulfill the criteria for CKD.
3. There is increasing recognition of the importance of proteinuria/albuminuria in the evaluation of kidney dysfunction in patients with HFrEF. Recent studies have identified that even modest increases in proteinuria/albuminuria are independently associated with the development of HFrEF and with morbidity and mortality in those with HFrEF.
4. Those with CKD and HFrEF experience worse outcomes on average, and they receive lower rates of GDMT.
5. Data for the benefits of angiontensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in HFrEF patients with advanced CKD are scarce and utilization of these therapies can yield dangerous side effects, but overall poor outcomes may result in a greater absolute therapeutic benefit.
6. Beta-blockers, although often beneficial in populations with comorbid CKD-HFrEF, require careful monitoring for side effects, particularly in patients nearing dialysis.
7. For patients with HFrEF and eGFR <30 ml/min/1.73 m²:
• No dose adjustment is required for fosinopril, candesartan (untested in eGFR <15 ml/min/1.73 m²), losartan, valsartan (untested in eGFR <10 ml/min/1.73 m²), carvedilol, and metoprolol succinate.
• A half dose initially for captopril, enalapril, lisinopril, trandolapril, and bisoprolol and a quarter dose initially for ramipril.
• Perindopril is not recommended, whereas spironolactone and eplerenone are contraindicated.
• An initial dose of sacubitril/valsartan 24 mg/26 mg is recommended and doubled every 2-4 weeks as tolerated; target dose is 97 mg/103 mg.
• It is recommended that blood pressure, serum potassium, and kidney function be monitored when prescribing/titrating ACE inhibitors, ARBs, or angiotensin-receptor/neprilysin inhibitors (ARNIs) and blood pressure, heart rate, and blood glucose in patients with diabetes mellitus be monitored when prescribing/titrating beta-blockers.
8. Novel potassium binders such as patiromer and sodium zirconium cyclosilicate may mitigate the hyperkalemia associated with RAS inhibitor, but such therapies also require consideration of potential adverse events, such as binding of concurrent oral medications, gastrointestinal upset, hypomagnesemia with patiromer, and worsening edema from an increased sodium load with sodium zirconium cyclosilicate.
9. Device therapy is an area of continued controversy in such patients, as multiple trials have shown benefit in patient populations with HFrEF, but application to the advanced CKD population is less clear. In this population, factors such as life expectancy and periprocedural risk must be balanced when considering the potential benefit of device therapy.
10. Adequately powered clinical trials with careful adverse event monitoring and follow-up are required to evaluate the benefits of GDMT in populations with comorbid CKD-HFrEF.

Perspective: This is an important review because it gives guidance on management of patients with comorbid CKD-HFrEF.

Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Albuminuria, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Creatinine, Diabetes Mellitus, Edema, Geriatrics, Glomerular Filtration Rate, Heart Failure, Hyperkalemia, Kidney Diseases, Renal Dialysis, Renal Insufficiency, Chronic, Secondary Prevention, Stroke Volume

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