What is the initial pharmacological treatment for a patient with heart failure with reduced ejection fraction (HFrEF)?

Case Study: Heart Failure with Reduced Ejection Fraction

Patient Presentation

Chief Complaint: 58-year-old male presents with progressive dyspnea on exertion over 3 months, orthopnea requiring 3 pillows, and bilateral lower extremity edema.

History:

• Anterior wall myocardial infarction 6 months ago treated with percutaneous coronary intervention
• Hypertension for 10 years
• Type 2 diabetes mellitus
• Current medications: aspirin, atorvastatin, metformin
• No prior heart failure diagnosis or treatment

Physical Examination:

• Blood pressure: 110/70 mmHg, Heart rate: 92 bpm, regular
• Jugular venous pressure elevated at 10 cm H2O
• Bibasilar crackles on lung auscultation
• S3 gallop present
• 2+ pitting edema to mid-shin bilaterally

Diagnostic Studies:

• Echocardiogram: LVEF 28%, dilated left ventricle, no significant valvular disease
• BNP: 850 pg/mL
• Creatinine: 1.2 mg/dL (eGFR 65 mL/min/1.73m²)
• Potassium: 4.2 mEq/L
• ECG: Sinus rhythm, QRS duration 100 ms

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Internal Board Questions

Question 1: Initial Pharmacological Management

What are the four foundational medication classes that should be initiated as soon as possible after diagnosis in this patient?

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The four foundational medication classes ("four pillars") that must be initiated rapidly are: (1) ACE inhibitor or ARNI, (2) beta-blocker, (3) mineralocorticoid receptor antagonist (MRA), and (4) SGLT2 inhibitor. 1

Specific drug selection and dosing for this patient:

• ACE Inhibitor: Start enalapril 2.5 mg twice daily or lisinopril 5 mg daily, titrate every 2 weeks to target doses (enalapril 10 mg twice daily or lisinopril 20-40 mg daily) 2

• Beta-blocker: Initiate carvedilol 3.125 mg twice daily, bisoprolol 1.25 mg daily, or metoprolol succinate 12.5-25 mg daily; up-titrate every 2 weeks to target doses (carvedilol 25-50 mg twice daily, bisoprolol 10 mg daily, or metoprolol succinate 200 mg daily) 2, 1

• MRA: Add spironolactone 25 mg daily or eplerenone 25 mg daily after ACE inhibitor and beta-blocker are established; monitor potassium and creatinine within 1 week, then monthly for 3 months 2, 1

• SGLT2 Inhibitor: Start dapagliflozin 10 mg daily or empagliflozin 10 mg daily regardless of diabetes status 1, 3

• Diuretic: Furosemide 20-40 mg daily for symptom relief given signs of congestion (crackles, edema, elevated JVP) 2

Critical implementation points:

• All four foundational classes should be initiated as soon as possible, not sequentially 1, 4
• Start at low doses and titrate to target doses proven in clinical trials 2, 4
• Monitor blood pressure, renal function, and potassium closely during initiation and titration 2, 3
• Avoid NSAIDs which can worsen renal function and reduce ACE inhibitor efficacy 2

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Question 2: Persistent Symptoms Despite Optimal Therapy

After 3 months, the patient remains on target doses of ACE inhibitor (enalapril 10 mg twice daily), beta-blocker (carvedilol 25 mg twice daily), MRA (spironolactone 25 mg daily), and SGLT2 inhibitor (dapagliflozin 10 mg daily). He continues to have NYHA Class III symptoms with dyspnea on minimal exertion. Blood pressure is 108/68 mmHg, creatinine 1.3 mg/dL, potassium 4.5 mEq/L. What is the next pharmacological intervention?

Click for Answer

Replace the ACE inhibitor with sacubitril/valsartan (ARNI) to further reduce the risk of heart failure hospitalization and death. 2, 5, 1

Specific transition protocol:

• Mandatory 36-hour washout: Discontinue enalapril and wait exactly 36 hours before initiating sacubitril/valsartan to avoid angioedema risk 5, 6

• Starting dose: Begin sacubitril/valsartan 49/51 mg twice daily (this patient was on high-dose ACE inhibitor) 5, 6

• Titration schedule: Double the dose every 2-4 weeks as tolerated to target dose of 97/103 mg twice daily 5, 6

• Monitoring during transition:

  • Blood pressure before each dose increase (hold if systolic BP <100 mmHg with symptoms) 5, 3
  • Renal function and potassium within 1-2 weeks of initiation and after each dose increase 5
  • Consider reducing diuretic dose if patient develops symptomatic hypotension without congestion 5

Evidence supporting this intervention:

• The PARADIGM-HF trial demonstrated sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization by 20% (HR 0.80,95% CI 0.73-0.87, p<0.0001) compared to enalapril 6
• All-cause mortality was reduced by 16% (HR 0.84,95% CI 0.76-0.93, p=0.0009) 6
• Sacubitril/valsartan is specifically recommended for patients who remain symptomatic despite optimal therapy with ACE inhibitor, beta-blocker, and MRA 2, 5

Common pitfalls to avoid:

• Do not skip the 36-hour washout period—this is mandatory to prevent life-threatening angioedema 5, 6
• Do not permanently reduce dose due to asymptomatic hypotension; temporary dose reduction with subsequent re-titration is preferred 5
• Do not withhold therapy in patients with systolic BP 100-110 mmHg if asymptomatic; these patients often tolerate and benefit from treatment 5
• Do not use concomitantly with ACE inhibitors or ARBs 6

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Question 3: Managing Hypotension During Optimization

Two weeks after starting sacubitril/valsartan 49/51 mg twice daily, the patient reports dizziness when standing. Blood pressure is 92/58 mmHg sitting, 85/55 mmHg standing. He has no orthopnea, no edema, clear lungs, and flat jugular veins. Creatinine is stable at 1.3 mg/dL. How should you manage this situation?

Click for Answer

Reduce the diuretic dose first (or discontinue if no signs of congestion), maintain all guideline-directed medical therapy including sacubitril/valsartan at current dose, and reassess in 1-2 weeks. 5, 3

Specific management algorithm:

1. Assess volume status carefully:

   • No congestion present (clear lungs, no edema, flat JVP) indicates diuretic reduction is safe 5
   • Symptomatic hypotension with orthostasis but stable renal function suggests volume depletion, not medication intolerance 3

2. Adjust diuretics, not GDMT:

   • Reduce furosemide by 50% or hold completely if no congestion 5, 3
   • Continue sacubitril/valsartan 49/51 mg twice daily without reduction 5
   • Maintain beta-blocker, MRA, and SGLT2 inhibitor at current doses 3

3. Patient counseling:

   • Explain that asymptomatic low blood pressure (systolic BP 85-100 mmHg) is expected and beneficial with GDMT 5
   • Advise slow position changes, adequate hydration, and avoiding hot environments 3
   • Symptomatic hypotension requires intervention, but asymptomatic hypotension does not 5

4. Follow-up plan:

   • Reassess in 1-2 weeks after diuretic adjustment 5
   • If symptoms resolve, attempt to up-titrate sacubitril/valsartan to target dose 97/103 mg twice daily 5
   • If symptomatic hypotension persists despite diuretic reduction, consider temporary dose reduction of sacubitril/valsartan to 24/26 mg twice daily with plan to re-titrate 5

Critical principle: Diuretics provide symptom relief but do not improve mortality, while sacubitril/valsartan, beta-blockers, MRAs, and SGLT2 inhibitors reduce mortality and hospitalization 2, 5. Therefore, reduce or eliminate diuretics before reducing life-saving GDMT 5, 3.

What NOT to do:

• Do not discontinue sacubitril/valsartan for asymptomatic hypotension 5
• Do not reduce beta-blocker dose unless heart rate is <50 bpm with symptoms 3
• Do not reduce MRA or SGLT2 inhibitor for hypotension alone 3
• Do not accept medium-range doses as adequate; 40% of patients requiring temporary dose reduction can be successfully re-titrated to target doses 5

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Question 4: Hyperkalemia Management

Six weeks later, the patient is on sacubitril/valsartan 97/103 mg twice daily, carvedilol 25 mg twice daily, spironolactone 25 mg daily, and dapagliflozin 10 mg daily. Routine labs show potassium 5.8 mEq/L, creatinine 1.4 mg/dL (eGFR 58 mL/min/1.73m²). He is asymptomatic with NYHA Class II symptoms. What is the appropriate management?

Click for Answer

Reduce or discontinue the MRA temporarily, maintain all other GDMT, initiate dietary potassium restriction, and consider potassium binders to allow continuation of life-saving therapy. 3, 4

Specific management strategy:

1. Immediate intervention for potassium 5.5-6.0 mEq/L:

   • Reduce spironolactone to 12.5 mg daily or hold for 3-7 days 3
   • Maintain sacubitril/valsartan, beta-blocker, and SGLT2 inhibitor at current doses 3
   • Recheck potassium in 3-7 days 3

2. Dietary and medication review:

   • Restrict dietary potassium intake (<2-3 g/day) 3
   • Discontinue potassium supplements if prescribed 3
   • Avoid NSAIDs, potassium-sparing diuretics other than MRA, and trimethoprim 3
   • Review for potassium-containing salt substitutes 3

3. Consider potassium binders:

   • Patiromer 8.4 g daily or sodium zirconium cyclosilicate 10 g daily allows continuation of MRA therapy 3
   • These agents permit optimal GDMT dosing in patients with recurrent hyperkalemia 3

4. Re-challenge protocol:

   • Once potassium <5.0 mEq/L, restart spironolactone 12.5 mg daily 3
   • Monitor potassium weekly for 4 weeks, then monthly 3
   • If potassium remains <5.5 mEq/L, consider increasing to 25 mg daily with continued monitoring 3

Critical considerations:

• Do not discontinue sacubitril/valsartan for hyperkalemia; the MRA provides additional but less critical mortality benefit 2, 3
• Mild hyperkalemia (5.5-6.0 mEq/L) without ECG changes can be managed with dose adjustment rather than complete discontinuation 3
• The combination of ARNI + MRA increases hyperkalemia risk, but this should not prevent use of both medications 2, 3

What NOT to do:

• Do not discontinue sacubitril/valsartan as first-line intervention 3
• Do not add an ARB to the combination of sacubitril/valsartan and MRA (triple RAS blockade increases hyperkalemia risk) 2
• Do not accept suboptimal GDMT dosing without attempting potassium binders or dietary modification 3

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Question 5: Device Therapy Consideration

After 6 months of optimal medical therapy (sacubitril/valsartan 97/103 mg twice daily, carvedilol 50 mg twice daily, spironolactone 25 mg daily, dapagliflozin 10 mg daily), the patient has NYHA Class II symptoms. Repeat echocardiogram shows LVEF 32%, QRS duration remains 100 ms with normal morphology. Is this patient a candidate for device therapy?

Click for Answer

Yes, this patient meets criteria for an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death, but does NOT meet criteria for cardiac resynchronization therapy (CRT). 2, 1

ICD indication analysis:

Criteria met:

• LVEF ≤35% (patient has 32%) 2, 1
• Symptomatic heart failure (NYHA Class II) 2, 1
• Optimal medical therapy for ≥3 months 2, 1
• Life expectancy >1 year with good functional status 2
• At least 40 days post-myocardial infarction 2

Recommendation: ICD is indicated (Class I recommendation) to reduce risk of sudden death and all-cause mortality 2, 1

CRT indication analysis:

Criteria NOT met:

• QRS duration 100 ms (CRT requires QRS ≥130 ms with LBBB morphology for Class I indication) 1
• Normal QRS morphology (not LBBB) 1

Recommendation: CRT is NOT indicated at this time; patient does not meet electrical dyssynchrony criteria 1

Implementation considerations:

• Ensure patient has been on stable, optimal GDMT for at least 3 months before ICD implantation 2
• Re-evaluate LVEF after 3-6 months of optimal medical therapy, as some patients experience significant improvement that may obviate need for ICD 1
• If LVEF improves to >35%, ICD may not be necessary for primary prevention 2
• Discuss risks, benefits, and patient preferences regarding device therapy 1

Future monitoring:

• If patient develops LBBB with QRS ≥130 ms in the future, reassess for CRT-D (combined CRT and ICD) 1
• Annual echocardiogram to monitor LVEF and ventricular remodeling 2

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Key Learning Points

Foundational therapy: All four medication classes (ARNI/ACE inhibitor, beta-blocker, MRA, SGLT2 inhibitor) should be initiated rapidly, not sequentially, to maximize mortality benefit 1, 4

Sacubitril/valsartan: Replace ACE inhibitor with ARNI in patients remaining symptomatic despite optimal therapy; requires mandatory 36-hour washout from ACE inhibitor 2, 5, 6

Hypotension management: Reduce diuretics first before reducing life-saving GDMT; asymptomatic hypotension is expected and beneficial 5, 3

Hyperkalemia management: Adjust MRA dose and use potassium binders rather than discontinuing ARNI or beta-blocker 3, 4

Device therapy: ICD indicated for LVEF ≤35% after ≥3 months optimal medical therapy; CRT requires QRS ≥130 ms with LBBB 2, 1