What is the recommended initial treatment for a patient with heart failure with reduced ejection fraction (HFrEF) and impaired renal function?

Initial Treatment for HFrEF with Impaired Renal Function

Start all four foundational medication classes simultaneously as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor if ARNI not tolerated), along with loop diuretics for volume management—this quadruple therapy provides approximately 73% mortality reduction and should NOT be delayed or withheld due to impaired renal function alone. 1

First-Line Quadruple Therapy Algorithm

Step 1: Initiate SGLT2 Inhibitor and MRA First

• Start with SGLT2 inhibitor (dapagliflozin or empagliflozin) and MRA (spironolactone or eplerenone) as your first agents because they have minimal blood pressure effects, making them ideal for patients with renal impairment who may have borderline BP 1
• SGLT2 inhibitors reduce cardiovascular death and HF hospitalization regardless of diabetes status, with benefits occurring within weeks 1
• SGLT2 inhibitors can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin, or ≥20 mL/min/1.73 m² for dapagliflozin 1, 2
• MRAs can be used if eGFR >30 mL/min/1.73 m²—start with low dose (6.25-12.5 mg spironolactone daily or 12.5 mg every other day) 1, 2
• MRAs provide at least 20% mortality reduction and reduce sudden cardiac death 1

Step 2: Add Beta-Blocker

• Initiate evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) at low dose 1, 3
• Beta-blockers reduce mortality by at least 20% and decrease sudden cardiac death 1
• Of the three recommended beta-blockers, only bisoprolol may accumulate in renal impairment, but patients should still be titrated to target dose (10 mg daily) or maximally tolerated dose 2
• Beta-blockers should be initiated as soon as possible—early initiation produces survival benefits and improves long-term compliance 4

Step 3: Initiate ARNI or ACE Inhibitor

• Start sacubitril/valsartan (ARNI) as preferred first-line therapy over ACE inhibitors—provides superior mortality reduction of at least 20% compared to ACE inhibitors 1
• ARNI is not recommended if eGFR <30 mL/min/1.73 m²—use ACE inhibitor instead in this population 2
• For ARNI dosing with renal impairment: start 24/26 mg twice daily if eGFR 30-60 mL/min/1.73 m² 5, 6
• If using ACE inhibitor instead: start low dose and uptitrate to target doses shown effective in large trials 7

Step 4: Add Loop Diuretics for Volume Management

• Loop diuretics are essential for congestion control but do not reduce mortality—use furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily 1
• If GFR <30 mL/min, do not use thiazides except synergistically with loop diuretics 7
• Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 1

Titration Strategy for Renal Impairment

Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1

• Start with SGLT2 inhibitor and MRA first (minimal BP effects), then add beta-blocker, then ARNI 1
• Target doses: ARNI 97/103 mg twice daily, carvedilol 25 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily, spironolactone 25-50 mg daily 7, 1
• Higher doses of these medications are associated with better clinical outcomes—accepting suboptimal doses is a common pitfall to avoid 1, 3

Critical Monitoring Requirements

Renal Function Monitoring

• Check serum creatinine, eGFR, and potassium at 1-2 weeks after each dose increment 7, 1
• More frequent monitoring required in patients with past or present renal dysfunction 7
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should NOT prompt discontinuation—this represents hemodynamic adjustment, not nephrotoxicity 1, 8
• RAAS blockers are not nephrotoxic drugs—they only have a functional effect on renal function 8

Potassium Monitoring

• Monitor potassium closely when using MRAs, especially with concurrent ARNI or ACE inhibitor 1, 2
• Start MRA with 1-week low-dose administration, check potassium and creatinine after 5-7 days, recheck every 5-7 days until stable 7
• If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications 1
• Discontinuing RAAS inhibitors after hyperkalemia is associated with two to fourfold higher risk of subsequent adverse events 1

Managing Worsening Renal Function

Before Changing Treatment, Assess:

1. Concomitant disorders that could alter renal function: infection, diarrhea, hyperthermia 8
2. Volume status: congestion vs. dehydration 8
3. Blood pressure adequacy 8
4. Nephrotoxic drug intake: NSAIDs, alpha-blockers, other non-essential medications 7, 1, 8

Key Principle:

An initial decline in eGFR on initiation of RAAS inhibitors/ARNI/MRAs/SGLT2 inhibitors is expected—renal function often stabilizes over time, and drugs maintain clinical efficacy 9

A decline in eGFR in the context of stable or improving clinical condition should NOT lead to discontinuation of life-saving HFrEF therapies 9

Special Considerations for Low Blood Pressure

• Do NOT withhold therapy for asymptomatic low BP with adequate perfusion—GDMT maintains efficacy and safety even with baseline SBP <110 mmHg 1
• If symptomatic hypotension occurs (SBP <80 mmHg or major symptoms):
  1. Address reversible non-HF causes first: stop alpha-blockers, discontinue non-essential BP-lowering medications, evaluate for dehydration/infection 1
  2. Use non-pharmacological interventions: compression leg stockings, adequate salt/fluid intake if not volume overloaded 1
  3. Only if symptoms persist: reduce GDMT in specific order—if HR >70 bpm reduce ARNI/ACE inhibitor dose first; if HR <60 bpm reduce beta-blocker dose first 1
  4. Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1

Contraindications Specific to Renal Impairment

• Bilateral renal artery stenosis: absolute contraindication to ACE inhibitors/ARNI 7
• eGFR <30 mL/min/1.73 m²: avoid ARNI, use ACE inhibitor instead 2
• eGFR <30 mL/min/1.73 m²: avoid MRAs 1, 2
• eGFR <20-30 mL/min/1.73 m²: SGLT2 inhibitor efficacy varies by agent (dapagliflozin ≥20, empagliflozin ≥30) 1, 2
• Avoid potassium-sparing diuretics during ACE inhibitor initiation 7
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—start simultaneously, not sequentially 1
2. Accepting suboptimal doses due to mild laboratory changes—target doses provide maximum benefit 1, 3
3. Stopping medications for asymptomatic hypotension or modest creatinine elevation—these are expected hemodynamic effects 1, 9
4. Inadequate monitoring leading to preventable complications 1
5. Using non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate)—only use carvedilol, metoprolol succinate, or bisoprolol 1
6. Permanent dose reductions when temporary reductions with subsequent re-titration would be appropriate 1
7. Withholding RAAS blockers due to misunderstanding their functional (not nephrotoxic) effect on kidneys 8