What medications should be started in a patient with a reduced ejection fraction (EF) of 35%, chronic kidney disease (CKD), and presenting with breathlessness?

Medications for HFrEF (EF 35%) with CKD and Breathlessness

Start triple neurohormonal blockade immediately: an ACE inhibitor (or ARB if intolerant), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), along with a loop diuretic for congestion relief. 1

Immediate Management

Loop Diuretics (First Priority for Symptom Relief)

• Loop diuretics are recommended immediately to relieve breathlessness and congestion in this symptomatic patient 1
• Use furosemide 20-80 mg twice daily, bumetanide 0.5-2 mg twice daily, or torsemide 5-10 mg once daily 1
• Loop diuretics are preferred over thiazides in patients with moderate-to-severe CKD (eGFR <30 mL/min) 1
• Monitor urine output, renal function, and electrolytes regularly after initiation 1

Foundational Therapy (Guideline-Directed Medical Therapy)

ACE Inhibitor or ARB

• An ACE inhibitor is recommended in addition to a beta-blocker for all symptomatic HFrEF patients to reduce hospitalization and death 1
• Start as soon as blood pressure and renal function permit, even during acute presentation 1
• If ACE inhibitor is not tolerated due to cough or angioedema, substitute with an ARB 1
• ACE inhibitors and ARBs are safe and effective in CKD up to stage 3B (eGFR ≥30 mL/min/1.73 m²) 2, 3
• Monitor potassium and creatinine 1-2 weeks after initiation; an initial decline in eGFR is expected and should not prompt discontinuation if the patient is clinically stable 1, 3
• Do NOT combine ACE inhibitor + ARB + MRA due to excessive risk of hyperkalemia and renal dysfunction 1

Beta-Blocker

• A beta-blocker is recommended in addition to an ACE inhibitor for stable symptomatic HFrEF to reduce hospitalization and death 1
• Start after initial stabilization of congestion, but can be initiated before discharge 1
• Use bisoprolol 2.5-10 mg once daily, carvedilol 12.5-50 mg twice daily, or metoprolol succinate 50-200 mg once daily 1
• Beta-blockers improve outcomes in HFrEF across all stages of CKD, including dialysis patients 2, 4
• Uptitrate dose as tolerated before discharge, with plan to complete titration after discharge 1

Mineralocorticoid Receptor Antagonist (MRA)

• An MRA is recommended for patients who remain symptomatic despite ACE inhibitor and beta-blocker to reduce hospitalization and death 1
• Use spironolactone 25-100 mg once daily or eplerenone 50-100 mg once or twice daily 1
• Start as soon as renal function and potassium permit; MRA has minimal blood pressure effect, so can be started even in relatively hypotensive patients 1
• Exercise extreme caution in CKD: avoid if potassium >5.0 mmol/L or eGFR <30 mL/min/1.73 m² 1
• Monitor potassium and creatinine closely; discontinue if potassium >6.0 mmol/L 1
• Avoid concomitant potassium supplements, potassium-sparing diuretics, and NSAIDs 1

Advanced Therapy Considerations

Sacubitril/Valsartan (ARNI)

• Sacubitril/valsartan is recommended as replacement for ACE inhibitor to further reduce hospitalization and death in ambulatory patients who remain symptomatic despite optimal therapy 1
• Can be used in patients with eGFR as low as 20 mL/min/1.73 m² 2, 5
• In advanced CKD (stages 4-5), sacubitril/valsartan is effective but requires close monitoring of eGFR and potassium 5
• Must ensure 36-hour washout period from ACE inhibitor before initiating 6

SGLT2 Inhibitors

• SGLT2 inhibitors improved mortality and hospitalization in HFrEF with CKD stages 3 and 4 (eGFR >20 mL/min/1.73 m²) 2, 3
• Safe and effective up to CKD stage 3B for reducing cardiovascular death and heart failure hospitalization 3

Critical Monitoring in CKD

• Check renal function (creatinine, eGFR) and electrolytes (potassium, sodium) at baseline, 1-2 weeks after each medication initiation or dose change 1
• An initial decline in eGFR with ACE inhibitor/ARB/MRA/ARNI is expected and acceptable if patient remains clinically stable; do not discontinue therapy for this reason alone 3
• Target potassium <5.5 mmol/L; if potassium rises to 5.5-6.0 mmol/L, reduce MRA dose; if >6.0 mmol/L, discontinue MRA 1
• Avoid nephrotoxic agents (NSAIDs) and high-potassium salt substitutes 1

Medications to AVOID

• Do NOT use diltiazem or verapamil in HFrEF as they increase risk of worsening heart failure and hospitalization 1, 7
• Do NOT combine ACE inhibitor + ARB + MRA due to excessive hyperkalemia and renal dysfunction risk 1
• Avoid thiazide diuretics if eGFR <30 mL/min/1.73 m² (ineffective); use loop diuretics instead 1