What is the best management approach for a 63-year-old female patient with Heart Failure with Reduced Ejection Fraction (HFrEF) of 23%?

Management of HFrEF with 23% Ejection Fraction in a 63-Year-Old Female

This patient requires immediate initiation of quadruple guideline-directed medical therapy (GDMT) consisting of: (1) an ARNI (sacubitril-valsartan) or ACE inhibitor, (2) an evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and (4) an SGLT2 inhibitor (dapagliflozin or empagliflozin), initiated simultaneously at low doses with rapid uptitration as tolerated. 1, 2

Foundational Quadruple Therapy - Start All Four Pillars Early

The contemporary approach emphasizes early initiation of all four medication classes rather than sequential uptitration of one drug before starting another. 1, 2, 3

First Pillar: RAAS Inhibition

• Start with sacubitril-valsartan (ARNI) as first-line therapy over ACE inhibitors, as it provides superior reduction in cardiovascular death and heart failure hospitalization (20% relative risk reduction). 1, 4
• If ARNI is not immediately available or affordable, initiate an ACE inhibitor (enalapril, lisinopril, or ramipril) and transition to ARNI once stable. 1
• ARBs are reserved only for patients truly intolerant to both ACE inhibitors and ARNI. 1
• For this 63-year-old female specifically: Women derive similar mortality benefits from ARNI as men, with the PARADIGM-HF trial showing equivalent cardiovascular death reduction in both sexes. 1

Second Pillar: Beta-Blockers

• Initiate one of three evidence-based beta-blockers: carvedilol, metoprolol succinate extended-release, or bisoprolol—these are the only beta-blockers proven to reduce mortality in HFrEF. 1
• Start at very low doses (e.g., carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily) and uptitrate gradually every 2 weeks as tolerated. 1
• Beta-blockers reduce both sudden cardiac death and pump failure death, with women showing similar or potentially greater benefit than men in reducing heart failure hospitalizations. 1
• Do not delay beta-blocker initiation waiting for ACE inhibitor uptitration—adding a beta-blocker to low-dose ACE inhibitor produces greater benefit than increasing ACE inhibitor dose alone. 1

Third Pillar: Mineralocorticoid Receptor Antagonists (MRAs)

• Start spironolactone 25 mg daily (or 12.5 mg daily if concerns about hyperkalemia exist). 5
• Spironolactone reduced all-cause mortality by 30% in the RALES trial for patients with NYHA class III-IV symptoms and EF ≤35%. 5
• Monitor potassium and creatinine closely: baseline potassium must be ≤5.0 mEq/L and creatinine ≤2.5 mg/dL to initiate safely. 5
• Women may derive particular benefit: pooled analysis suggests similar or greater mortality reduction in women compared to men with MRA therapy. 1

Fourth Pillar: SGLT2 Inhibitors

• Initiate dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately—these are unique among HFrEF medications as they require no uptitration, don't affect blood pressure or heart rate, and provide rapid benefit within weeks. 1, 4, 3
• SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalization by approximately 25%, regardless of diabetes status, age, sex, or background medical therapy. 1, 4
• Benefits occur even in patients receiving <50% of target doses of other GDMT medications, making them ideal for early initiation. 1
• Safe with eGFR ≥20 mL/min/1.73 m² for dapagliflozin and ≥30 mL/min/1.73 m² for empagliflozin. 1
• SGLT2 inhibitors reduce hyperkalemia risk and facilitate use of MRAs. 1

Practical Implementation Strategy

Simultaneous Low-Dose Initiation Approach

Start all four medications at low doses simultaneously rather than sequentially—this modern approach achieves comprehensive therapy faster and improves outcomes. 1, 2, 3

Example starting regimen:

• Sacubitril-valsartan 24/26 mg twice daily (or enalapril 2.5 mg twice daily)
• Carvedilol 3.125 mg twice daily (or metoprolol succinate 12.5-25 mg daily)
• Spironolactone 12.5-25 mg daily
• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily
• Loop diuretic (furosemide 20-40 mg daily) as needed for congestion 1

Uptitration Schedule

• Uptitrate every 1-2 weeks as tolerated, monitoring blood pressure, heart rate, potassium, and creatinine. 1, 3
• Target doses: sacubitril-valsartan 97/103 mg twice daily, carvedilol 25 mg twice daily (or metoprolol succinate 200 mg daily), spironolactone 25-50 mg daily. 1, 5
• SGLT2 inhibitors require no uptitration—the starting dose is the therapeutic dose. 1

Monitoring Parameters

• Check potassium and creatinine within 1-2 weeks after initiating or uptitrating RAAS inhibitors or MRAs. 1
• Accept mild creatinine increases (up to 30% from baseline) if patient is decongesting and not showing signs of true tubular injury—this often represents hemodynamic changes, not kidney damage. 1
• Tolerate systolic blood pressure down to 90 mmHg if patient is asymptomatic—low blood pressure does not preclude GDMT use and should not trigger dose reductions. 1
• Monitor heart rate: target 50-60 bpm with beta-blockers, but bradycardia to 50 bpm is acceptable if asymptomatic. 1

Special Considerations for Women

• Women are significantly undertreated with GDMT despite deriving equal or greater benefit than men across all medication classes. 1
• Women may experience higher rates of angioedema with ARNI due to higher bradykinin production after neprilysin inhibition—monitor closely but don't avoid therapy. 1
• Beta-blocker benefits in women are equivalent to men for mortality reduction, with potentially greater reductions in heart failure hospitalizations. 1
• At age 63, this patient is younger than typical heart failure trial populations (mean age 58-64 years in major trials), suggesting she may tolerate aggressive GDMT well. 1

Device Therapy Considerations

• Evaluate for implantable cardioverter-defibrillator (ICD) after ≥3 months of optimized GDMT if EF remains ≤35% and patient has NYHA class II-III symptoms with >1 year life expectancy. 1, 6
• Assess for cardiac resynchronization therapy (CRT) if QRS duration ≥150 ms with left bundle branch block morphology, sinus rhythm, and persistent symptoms despite GDMT. 1, 6
• Device decisions should be deferred until GDMT is optimized, as many patients experience EF improvement with medical therapy alone. 6

Common Pitfalls to Avoid

• Do not delay initiating all four pillars sequentially—the traditional approach of uptitrating one drug class before starting the next is outdated and delays benefit. 1, 2
• Do not withhold GDMT due to "low" blood pressure—patients with systolic BP 90-100 mmHg still benefit from therapy and often tolerate it well. 1
• Do not stop RAAS inhibitors or MRAs for mild creatinine increases during decongestion—distinguish hemodynamic changes from true acute tubular necrosis using clinical context and urine microscopy if needed. 1
• Do not use metoprolol tartrate (short-acting)—only metoprolol succinate extended-release is proven effective in HFrEF. 1
• Do not assume older age precludes aggressive therapy—while major trials had limited patients >75 years, benefits extend to older populations when therapy is tolerated. 1

Additional Therapies for Selected Patients

If symptoms persist despite optimized quadruple therapy:

• Ivabradine if heart rate ≥70 bpm despite maximum tolerated beta-blocker dose, in sinus rhythm. 4, 3
• Hydralazine-isosorbide dinitrate particularly for African American patients or those intolerant to ARNI/ACE inhibitor/ARB. 4, 3
• Vericiguat for high-risk patients with recent heart failure hospitalization or elevated natriuretic peptides despite GDMT. 4

Diuretic Management

• Use loop diuretics (furosemide, torsemide, bumetanide) only as needed to relieve congestion—they improve symptoms but don't modify disease progression or mortality. 1, 7
• Titrate diuretic dose to achieve euvolemia, then use the minimum dose necessary to maintain dry weight. 1
• Aggressive diuresis may cause transient creatinine increases—this is acceptable if achieving decongestion and not accompanied by signs of tubular injury. 1

The goal is to achieve target or maximum tolerated doses of all four GDMT pillars within 3-6 months, with most patients able to tolerate 85% reaching target doses when a cautious, systematic approach is used. 1, 2