In a patient with newly diagnosed heart failure with reduced ejection fraction, what is the initial management, what are the contraindications of angiotensin‑converting‑enzyme inhibitors, what monitoring is required, and what alternative regimen should be used if ACE inhibitors are contraindicated?

Initial Management of Newly Diagnosed HFrEF

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 over 2 years. 1

Specific Initial Regimen

First-Line Medications (Start Together)

• SGLT2 Inhibitor: Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily—no titration required, provides maximal benefit at starting dose, minimal blood pressure effect 1, 2

• Mineralocorticoid Receptor Antagonist: Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily—provides at least 20% mortality reduction, minimal blood pressure effect 1, 2

• Beta-Blocker: Carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily—start low, titrate every 1-2 weeks to target doses (carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily) 1, 2

• ARNI (Preferred): Sacubitril/valsartan 24/26 mg twice daily initially, titrate to 97/103 mg twice daily—provides superior 20% mortality reduction compared to ACE inhibitors 1, 2

• Loop Diuretic: Furosemide 20-40 mg once or twice daily (or equivalent)—titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 1, 3

Titration Strategy

• Sequence: Start SGLT2 inhibitor and MRA first (minimal BP effects), then add beta-blocker or low-dose ARNI 1, 2
• Timing: Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose achieved 1, 2
• Priority: SGLT2 inhibitor and MRA first, then beta-blocker, then ARNI 2

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ACE Inhibitor Contraindications

Absolute Contraindications

• History of angioedema related to previous ACE inhibitor or ARB therapy 1
• Hypersensitivity to any ACE inhibitor component 1
• Concomitant use with ARNI—must have 36-hour washout period between stopping ACE inhibitor and starting ARNI to avoid angioedema risk 1, 2
• Concomitant use with aliskiren in patients with diabetes 1

Relative Contraindications & Cautions

• Bilateral renal artery stenosis or stenosis in a solitary kidney 4
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)—requires dose adjustment 4
• Hyperkalemia (potassium >5.2 mmol/L)—must be corrected before initiation 2
• Systolic blood pressure <100 mmHg—though asymptomatic hypotension with adequate perfusion is NOT a contraindication 1, 2
• Pregnancy—ACE inhibitors are teratogenic and absolutely contraindicated 4

Critical Pitfall to Avoid

• Do NOT withhold ACE inhibitors for asymptomatic low blood pressure with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg 1, 2

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Monitoring Requirements

Initial Phase (First 3 Months)

• Blood pressure: At 1-2 weeks after each dose increment 2
• Renal function (creatinine/eGFR): At 1-2 weeks after each dose increment—modest increases up to 30% above baseline are acceptable and should NOT prompt discontinuation 2
• Serum potassium: At 1-2 weeks after each dose increment, especially with MRA—target <5.0 mEq/L before initiating MRA, monitor closely 1, 2
• Clinical volume status: Daily weights, assess for congestion (edema, orthopnea, jugular venous distension) 1, 3
• Symptoms: NYHA functional class, dyspnea, fatigue, exercise tolerance 3

Maintenance Phase (After Stabilization)

• Blood pressure, renal function, electrolytes: Every 6 months 1
• NT-proBNP or BNP: Can be useful during diuretic titration to ensure congestion does not worsen 2
• LVEF reassessment: Regularly to assess response to therapy 1

Specific Monitoring Thresholds

• Hyperkalemia management: If potassium rises, consider potassium binders (patiromer) rather than discontinuing life-saving medications 2
• Worsening renal function: Interpret in context of decongestion—worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function 2

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Alternative Regimen if ACE Inhibitors Contraindicated

Primary Alternative: ARNI (Sacubitril/Valsartan)

ARNI is actually PREFERRED over ACE inhibitors as first-line therapy in symptomatic HFrEF patients, providing superior mortality reduction. 1, 2

• Dosing: Start 24/26 mg twice daily, titrate to 97/103 mg twice daily over 4-8 weeks 1, 2
• Advantages: At least 20% mortality reduction superior to ACE inhibitors, reduces cardiovascular death and HF hospitalization 1, 2
• Requirements: SBP >100 mmHg, eGFR >30 mL/min/1.73 m², potassium <5.2 mmol/L 2, 5

Secondary Alternative: ARB (Angiotensin Receptor Blocker)

If ARNI is not tolerated or contraindicated, use an ARB as the next alternative. 6, 3

• Options: Valsartan (target 160 mg twice daily), losartan (target 150 mg daily), or candesartan (target 32 mg daily) 6
• Evidence: ARBs are non-inferior to ACE inhibitors for mortality but may have slightly higher HF hospitalization rates 7
• Advantage: Lower angioedema risk compared to ACE inhibitors 7

Tertiary Alternative: Hydralazine/Isosorbide Dinitrate

If both ACE inhibitors and ARBs are contraindicated, use hydralazine/isosorbide dinitrate combination. 6, 1

• Dosing: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily, titrate to hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 1
• Evidence: Prolongs survival but may be inferior to ACE inhibitors for mortality 2
• Special indication: Particularly beneficial in self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 6, 1

Complete Quadruple Therapy Without ACE Inhibitor

The complete regimen when ACE inhibitor is contraindicated:

1. ARNI (sacubitril/valsartan) as RAAS inhibitor 1, 2
2. SGLT2 inhibitor (dapagliflozin or empagliflozin) 1, 2
3. MRA (spironolactone or eplerenone) 1, 2
4. Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) 1, 2
5. Loop diuretic for volume management 1, 3

Critical Contraindication to Avoid

• NEVER combine ACE inhibitor + ARB + MRA—this triple combination increases risk of hyperkalemia and renal dysfunction 2, 3
• NEVER combine ACE inhibitor with ARNI—requires 36-hour washout to avoid angioedema 1, 2