What is the optimal treatment plan for a patient with heart failure with reduced ejection fraction (HFrEF) and an ejection fraction of 45%?

Optimal Treatment for HFrEF with EF 45%

This patient requires immediate initiation of quadruple guideline-directed medical therapy (GDMT): an SGLT2 inhibitor, ACE inhibitor (or ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA), plus loop diuretics for congestion. 1, 2

Immediate Management of Acute Congestion

Diuretics for symptom relief:

• Loop diuretics are required immediately to reduce signs and symptoms of congestion (jugular venous distention, S3 gallop, crackles, edema, pulmonary venous congestion) 1
• Titrate diuretic dose to achieve euvolemia with the lowest achievable dose 1
• Monitor daily weights and adjust based on symptoms/signs of congestion 3

Core Pharmacotherapy Initiation Strategy

Start all four foundational medication classes simultaneously once hemodynamically stable:

First-Line Agents (Start These First):

SGLT2 Inhibitor:

• Initiate immediately if eGFR >20 mL/min/1.73 m² 2
• This drug has minimal blood pressure effects and provides rapid mortality benefit 2
• Continue regardless of diabetic status 4

Mineralocorticoid Receptor Antagonist (Spironolactone or Eplerenone):

• Recommended for all symptomatic patients with LVEF ≤35% despite ACE inhibitor and beta-blocker 1
• Start with spironolactone 12.5-25 mg daily 5
• Requires serum potassium <5.0 mmol/L and adequate renal function 1
• In the RALES trial, spironolactone reduced mortality by 30% (p<0.001) 5
• Check potassium and creatinine after 5-7 days, then recheck every 5-7 days until stable 2

Second-Line Agents (Add Within Days):

ACE Inhibitor (or ARNI/ARB if ACE inhibitor not tolerated):

• Start low-dose ACE inhibitor (e.g., lisinopril 2.5-5 mg daily) 1, 2, 6
• Consider sacubitril/valsartan (ARNI) as replacement for ACE inhibitor to further reduce risk of HF hospitalization and death in ambulatory patients who remain symptomatic 1
• In PARADIGM-HF, sacubitril/valsartan showed absolute 4.7% reduction in CV death or HF hospitalization (HR 0.80, p<0.001) compared to enalapril 1
• If using ARNI, start with low dose (24/26 mg twice daily) and ensure 36-hour washout from ACE inhibitor to avoid angioedema 1
• Uptitrate every 1-2 weeks to target doses proven in trials 2

Beta-Blocker:

• Start low-dose evidence-based beta-blocker once patient is euvolemic and hemodynamically stable 1, 2
• Use only bisoprolol, carvedilol, or metoprolol succinate (not tartrate) - these are the only beta-blockers with proven mortality benefit 7, 4
• For metoprolol succinate: start 12.5-25 mg once daily, target 200 mg once daily 7
• Administer in the morning rather than at night to minimize sleep disturbances 3
• Beta-blockers reduced mortality by 34% in MERIT-HF trial 7

Titration Protocol

Systematic uptitration approach:

• After achieving euvolemia, uptitrate one drug at a time using small increments every 1-2 weeks 2
• Check blood pressure, heart rate, renal function, and electrolytes 1-2 weeks after each increment 2
• Target doses: ACE inhibitor equivalent to enalapril 10 mg twice daily, beta-blocker to maximum tolerated or target dose, MRA 25-50 mg daily 1
• Only 17-29% of patients achieve target ACE inhibitor/ARB doses and 13-28% achieve target beta-blocker doses in real-world practice, but any dose is better than none 2, 8

Additional Therapies for Persistent Symptoms

If patient remains symptomatic despite optimal GDMT:

Ivabradine:

• Consider if patient is in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker dose 1, 9
• Start 2.5 mg twice daily if age ≥75 years, or 5 mg twice daily if age <75 years 1, 9
• In SHIFT trial, ivabradine reduced risk of HF hospitalization or CV death by 18% (HR 0.82, p<0.0001) 9

Hydralazine/Isosorbide Dinitrate:

• Consider in selected patients, particularly African Americans or those intolerant to ACE inhibitors/ARBs/ARNIs 1

Critical Monitoring Parameters

Baseline laboratory assessment:

• Complete blood count, urinalysis, fasting lipids, liver function, electrolytes, BUN, creatinine, glucose, TSH 2

After medication changes:

• Blood pressure, heart rate, renal function (creatinine, eGFR), and electrolytes at 1-2 weeks after each increment 2
• Regular checks of serum potassium and renal function according to clinical status when on MRA 1

Common Pitfalls to Avoid

Never discontinue GDMT for asymptomatic or mildly symptomatic low blood pressure - this compromises long-term outcomes and poor outcomes associated with side effects often stem from discontinuing therapy rather than the side effects themselves 1, 2

Avoid NSAIDs - they interfere with ACE inhibitor efficacy and worsen renal function 2

Don't use thiazides if GFR <30 mL/min unless combined synergistically with loop diuretics 2

Avoid excessive diuresis before starting ACE inhibitors - this can precipitate hypotension 2

Don't confuse metoprolol formulations - metoprolol tartrate and succinate are not interchangeable; only succinate has the evidence base for HFrEF 7

Don't add ARB to combination of ACE inhibitor and MRA - increased risk of renal dysfunction and hyperkalemia 1

Avoid diltiazem or verapamil - they increase risk of HF worsening and hospitalization 1

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Recommended for primary prevention if LVEF ≤35% after ≥3 months of optimal medical therapy, expected survival >1 year with good functional status, and ischemic heart disease (unless MI within prior 40 days) 1

Cardiac Resynchronization Therapy (CRT):

• Recommended if QRS duration ≥150 msec with left bundle branch block morphology, LVEF ≤35%, and symptomatic despite optimal medical therapy 1, 2

When to Refer for Advanced Therapy

Referral criteria include:

• Persistent low blood pressure with major symptoms despite optimization attempts 2
• Inability to uptitrate GDMT due to hemodynamic intolerance 2
• Refractory symptoms on optimal medical therapy 2
• Recurrent hospitalizations despite maximal therapy 8