What is the guideline‑directed medical therapy for an adult patient with heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%)?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction (LVEF ≤ 40%)

All adult patients with HFrEF (LVEF ≤ 40%) should be started on quadruple therapy—ARNI (or ACE-I/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—simultaneously at low doses after hemodynamic stabilization, then rapidly uptitrated to target doses every 1-2 weeks, as this approach reduces 2-year mortality by approximately 73% compared to no treatment. 1, 2

The Four Foundational Medication Classes

1. Renin-Angiotensin System Inhibition (First Priority)

ARNI (sacubitril/valsartan) is strongly preferred over ACE inhibitors or ARBs because it provides at least 20% mortality reduction compared to the 5-16% reduction seen with ACE-I/ARB alone. 2

• Starting dose: Sacubitril/valsartan 24/26 mg (marketed as "50 mg") twice daily 3
• Target dose: 97/103 mg (marketed as "200 mg") twice daily 3
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 2

If ARNI is not tolerated or unavailable:

• Use an ACE inhibitor (e.g., lisinopril 10 mg daily, target 40 mg daily) or ARB (e.g., losartan 50 mg daily, target 150 mg daily) 2
• ACE inhibitors and ARBs are Class 1, Level of Evidence A recommendations 1

2. Beta-Blockers (Second Priority)

Only three beta-blockers have proven mortality benefit—carvedilol, metoprolol succinate, or bisoprolol—each providing at least 20% mortality reduction. 1, 2

Dosing regimens: 2

• Carvedilol: Start 3.125 mg twice daily; target 25-50 mg twice daily
• Metoprolol succinate: Start 12.5-25 mg daily; target 200 mg daily
• Bisoprolol: Start 1.25 mg daily; target 10 mg daily

Initiation timing: Beta-blockers should be started after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents, at low doses in stable patients only. 1

Special consideration: If refractory hypertension is present, carvedilol is preferred due to its combined α1-β1-β2-blocking properties. 2

3. Mineralocorticoid Receptor Antagonists (Third Priority)

MRAs (spironolactone or eplerenone) provide at least 20% mortality reduction. 1, 2

Dosing: 2

• Spironolactone: Start 12.5-25 mg daily; target 25-50 mg daily
• Eplerenone: Start 25 mg daily; target 50 mg daily

Key difference: Spironolactone causes 5.7% higher rate of male gynecomastia compared to eplerenone, which can be avoided by using eplerenone. 2

4. SGLT2 Inhibitors (Fourth Priority—Newest Addition)

Dapagliflozin or empagliflozin have significant mortality benefits and are now the fourth pillar of HFrEF therapy. 1, 2, 4

Unique advantages of SGLT2 inhibitors: 2

• No blood pressure, heart rate, or potassium effects
• No dose titration required
• Treatment benefits occur within weeks of initiation
• Effective regardless of background therapy
• Safe in moderate kidney dysfunction (eGFR ≥30 mL/min/1.73 m² for empagliflozin; ≥20 mL/min/1.73 m² for dapagliflozin)

Standard dosing:

• Dapagliflozin: 10 mg once daily
• Empagliflozin: 10 mg once daily

Critical Implementation Strategy: Simultaneous Initiation

Start all four medication classes simultaneously at low initial doses rather than waiting to achieve target dosing of one before initiating the next. 1, 2 This approach directly addresses the massive treatment gap where less than 25% of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications. 2

Uptitration schedule: Increase doses every 1-2 weeks until target doses are achieved, checking blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment. 1, 2

Special Clinical Scenarios

Patients with Low Blood Pressure (SBP ~90 mmHg)

Medication sequencing for hypotensive patients: 2

1. Start SGLT2 inhibitor and MRA first because these have minimal blood pressure impact (SGLT2i lowers SBP by only 1.5 mmHg average, diminishing to <1 mmHg after 4 months) 2

2. Add beta-blocker only if resting heart rate >60 bpm; if heart rate ≤60 bpm, defer beta-blocker until after ARNI/ACE-I/ARB has been started 2

3. Add ARNI (or ACE-I/ARB) last in this sequence 2

Critical principle: Asymptomatic or mildly symptomatic low systolic blood pressure (80-100 mmHg) is not a justification for reducing or stopping GDMT when perfusion is adequate. 2 Never withhold GDMT for asymptomatic hypotension when organ perfusion is sufficient. 2

Hospitalized Patients

Continue GDMT except when hemodynamically unstable or contraindicated. 2 In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 2

Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion. 2

Initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrating based on urine output and congestion symptoms. 2

Elderly Patients (≥65 years)

All four cornerstone medication classes remain indicated in older adults, but perform more frequent monitoring of blood pressure, renal function, and electrolytes during dose uptitration to mitigate age-related tolerability issues. 2

Adjunctive Therapies (Not First-Line)

Ivabradine

Add ivabradine (5 mg twice daily, target 7.5 mg twice daily) only when:

• Patient is in sinus rhythm with NYHA class II-III symptoms
• Resting heart rate >70 bpm despite maximally tolerated beta-blocker therapy 2

Critical caveat: Only 25% of participants in the ivabradine trial were on optimal beta-blocker doses, emphasizing that beta-blocker uptitration to target doses must precede ivabradine. 2

Hydralazine-Isosorbide Dinitrate

For self-identified Black patients with NYHA Class III-IV symptoms, add hydralazine/isosorbide dinitrate to quadruple therapy. 2 This is not first-line therapy and is reserved for this specific population. 2

Loop Diuretics

Loop diuretics are indicated for relief of volume-overload symptoms but do not modify disease progression. 2 Add only if fluid overload is present. 2

Monitoring and Managing Common Barriers

Renal Function

Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ACE-I/ARB/ARNI. 2 Temporary reduction or hold only if substantial renal deterioration occurs. 2

Blood Pressure

Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 2 Do not discontinue any GDMT component while SBP remains >80 mmHg and perfusion is sufficient. 2

Electrolytes

Monitor potassium and creatinine levels closely, with more frequent monitoring in patients with renal dysfunction or electrolyte disturbances. 2

Symptomatic Side Effects

Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT. 2

Common Pitfalls to Avoid

1. Sequential rather than simultaneous initiation delays achievement of optimal therapy 2
2. Overreacting to laboratory changes such as modest creatinine elevation 2
3. Withholding therapy for asymptomatic hypotension when perfusion is adequate 2
4. Using non-evidence-based beta-blockers instead of the three proven agents 1
5. Avoiding calcium channel blockers, moxonidine, and alpha-adrenergic blockers as they may worsen HF outcomes 2

Follow-Up Strategy

Early follow-up within 7-14 days after medication changes is recommended, monitoring for: 2

• Changes in volume status and blood pressure
• Renal function and electrolytes
• Symptoms of worsening heart failure

Referral to HF specialty care for newly diagnosed HFrEF patients maximizes GDMT optimization, with multidisciplinary teams including pharmacists and nurses improving GDMT titration and adherence. 2

Patients with Improved Ejection Fraction

Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen, as discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration. 2