What is the appropriate evaluation and first-line guideline-directed medical therapy for a patient with heart failure with reduced ejection fraction?

Heart Failure with Reduced Ejection Fraction: Evaluation and First-Line Therapy

All patients with newly diagnosed HFrEF should be started on quadruple guideline-directed medical therapy consisting of an SGLT2 inhibitor, ARNI (or ACE inhibitor if ARNI not tolerated), beta-blocker, and mineralocorticoid receptor antagonist, initiated simultaneously or in rapid sequence, ideally before hospital discharge if presenting acutely. 1, 2

Initial Diagnostic Evaluation

Essential Diagnostic Tests

• Echocardiography to confirm left ventricular ejection fraction ≤40% and assess for structural abnormalities, valvular disease, and right ventricular function 1, 3
• Natriuretic peptide testing (BNP or NT-proBNP) with elevation above age-specific thresholds confirming the diagnosis 1, 3
• 12-lead ECG to identify arrhythmias, conduction abnormalities (especially QRS duration and morphology for future CRT consideration), and evidence of prior myocardial infarction 1
• Complete metabolic panel including serum creatinine, estimated GFR, sodium, and potassium before initiating therapy 4
• Complete blood count to assess for anemia 1

Etiology Assessment

• Coronary angiography or noninvasive stress testing to determine ischemic versus non-ischemic etiology, as this impacts device therapy decisions 1, 3
• Consider cardiac MRI if etiology remains unclear after initial workup 1

Foundational Quadruple Therapy Initiation

First-Line Medication Classes (Start All Four)

1. SGLT2 Inhibitor (Start First)

• Initiate immediately as it has minimal blood pressure effects, rapid onset of benefit (within weeks), and can be started during acute decompensation once hemodynamically stable 2, 5
• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily 1, 6
• No titration required; full dose from initiation 2

2. Mineralocorticoid Receptor Antagonist (Start Second)

• Spironolactone 12.5-25 mg daily (start lower dose in elderly or those with borderline renal function) 1, 4, 5
• Requires serum potassium <5.0 mEq/L and eGFR >30 mL/min/1.73m² 4
• Check potassium and creatinine at 4-6 days, then 1-2 weeks after initiation 4
• Target dose: 25-50 mg daily 2

3. ARNI or ACE Inhibitor (Start Third)

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily is preferred over ACE inhibitors for superior mortality reduction 1, 2
• If ARNI not tolerated or contraindicated, use ACE inhibitor: enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg daily, or ramipril 1.25-2.5 mg daily 4
• Never combine ACE inhibitor with ARNI due to angioedema risk 2
• Target doses: sacubitril/valsartan 97/103 mg twice daily; enalapril 10-20 mg twice daily; lisinopril 20-40 mg daily 2, 4

4. Beta-Blocker (Start Fourth, Once Euvolemic)

• Initiate only after patient is euvolemic and hemodynamically stable (no intravenous inotropes, systolic BP >90 mmHg, heart rate >50 bpm) 1, 4
• Evidence-based agents: carvedilol 3.125 mg twice daily, bisoprolol 1.25 mg daily, or metoprolol succinate 12.5-25 mg daily 1, 4
• Target doses: carvedilol 25-50 mg twice daily, bisoprolol 10 mg daily, metoprolol succinate 200 mg daily 2, 4

Diuretic Therapy for Symptom Management

• Loop diuretics (furosemide 20-40 mg daily or equivalent) for any evidence of volume overload: peripheral edema, jugular venous distension, orthopnea, or pulmonary rales 2, 4, 5
• Diuretics must always be combined with RAAS inhibition, never used as monotherapy 4, 5
• Titrate dose based on daily weights, symptoms, and physical examination findings 5
• For inadequate response, increase loop diuretic dose or give twice daily 4
• For refractory fluid retention, combine loop diuretic with thiazide (metolazone) with close monitoring 4

Medication Titration Protocol

Systematic Up-Titration Strategy

• Increase one medication at a time every 1-2 weeks using small increments until target doses achieved 1, 2
• Check blood pressure, heart rate, renal function (creatinine/eGFR), and electrolytes (potassium, sodium) 1-2 weeks after each dose increase 2, 4
• Modest increases in creatinine up to 30% above baseline are acceptable and should not prompt discontinuation 2
• If potassium rises to ≥5.5 mEq/L on MRA, reduce dose by 50% or discontinue if continues to rise 4

Managing Hypotension During Titration

• If systolic BP <90 mmHg with symptoms (dizziness, lightheadedness):
  • First, reduce or discontinue non-essential antihypertensives (calcium channel blockers, alpha-blockers) 1
  • Reassess diuretic dose and reduce if overdiuresed 1
  • Consider starting ARNI at very low dose (24/26 mg twice daily) or switching from standard dose ACE inhibitor to low-dose ARNI 1
  • Use selective β₁ receptor blockers (bisoprolol, metoprolol) rather than non-selective agents if BP remains problematic 1
  • If beta-blocker not tolerated, consider ivabradine as alternative for heart rate control (if sinus rhythm with HR >70 bpm) 1, 4

Critical Contraindications and Medications to Avoid

Absolute Contraindications

• Never combine ACE inhibitor with ARNI (36-hour washout required when switching) 2, 5
• Avoid triple RAAS blockade (ACE inhibitor + ARB + MRA) due to hyperkalemia and renal dysfunction risk 2, 5
• Bilateral renal artery stenosis, history of angioedema, and pregnancy are contraindications to ACE inhibitors and ARNIs 4

Medications That Worsen HFrEF

• NSAIDs should be avoided as they worsen renal function, promote fluid retention, and interfere with RAAS inhibitor efficacy 1, 2, 4, 5
• Calcium channel blockers (diltiazem, verapamil) increase heart failure worsening risk and should be avoided 4, 5
• Non-dihydropyridine calcium channel blockers have negative inotropic effects 5
• Thiazolidinediones (pioglitazone, rosiglitazone) cause fluid retention 1

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for primary prevention in patients with LVEF ≤35%, NYHA class II-III symptoms, on optimal medical therapy for ≥3 months, and life expectancy >1 year 1, 5
• Indicated for secondary prevention in survivors of cardiac arrest or sustained ventricular tachycardia causing hemodynamic instability 5

Cardiac Resynchronization Therapy (CRT)

• Strongly indicated for patients in sinus rhythm with LVEF ≤35%, NYHA class II-IV symptoms, QRS duration ≥150 msec, and left bundle branch block morphology 1, 5
• Consider in patients with QRS 120-149 msec with LBBB 1

Special Populations and Additional Therapies

Patients with Atrial Fibrillation

• Digoxin for rate control and symptom improvement (0.125-0.25 mg daily, lower in elderly) 4, 5
• Beta-blockers remain first-line for rate control 5

Patients with Persistent Symptoms Despite Quadruple Therapy

• Ivabradine if sinus rhythm with heart rate ≥70 bpm despite beta-blocker therapy 1, 6
• Hydralazine/isosorbide dinitrate particularly beneficial in African American patients or if ACE inhibitor/ARB/ARNI contraindicated 4, 6, 3
• Vericiguat for high-risk patients with recent worsening heart failure 6, 3

Iron Deficiency

• Intravenous iron replacement if ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20%, regardless of anemia status 6

Common Pitfalls to Avoid

• Inadequate uptitration to target doses: Most patients in real-world practice receive suboptimal doses; only 14% achieve triple therapy at adequate doses 7
• Delaying beta-blocker initiation: Should be started once euvolemic, not delayed until "stable for months" 4
• Stopping medications due to asymptomatic hypotension: Low blood pressure without symptoms does not require dose reduction 1
• Excessive diuresis: Overdiuresis causes hypotension and limits ability to uptitrate GDMT 1
• Failure to initiate all four medication classes: Each class provides independent mortality benefit 1, 2
• Inadequate monitoring: Must check renal function and electrolytes regularly during titration 2, 4