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

Guideline-Directed Medical Therapy for Adult Heart Failure with Reduced Ejection Fraction

All adults with chronic heart failure and LVEF ≤40% should be started on quadruple therapy—consisting of an ARNI (or ACE inhibitor/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—simultaneously at low doses and rapidly uptitrated to target doses within 2-4 weeks. 1

Core Four-Pillar Pharmacologic Strategy

The foundation of HFrEF treatment consists of four medication classes that, when used together, reduce 2-year mortality by approximately 73% compared to no treatment: 1

1. Renin-Angiotensin System Inhibition (First-Line: ARNI)

• Sacubitril/valsartan (ARNI) is strongly preferred over ACE inhibitors or ARBs, providing at least 20% mortality reduction versus the 5-16% reduction seen with ACE inhibitors/ARBs alone. 1
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily and uptitrate to the target dose of 97/103 mg twice daily. 2
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema. 1
• If ARNI is not tolerated or available, use an ACE inhibitor (e.g., lisinopril 10 mg daily, uptitrate to 40 mg daily) or ARB (e.g., losartan 50 mg daily, uptitrate to 150 mg daily). 3, 1

2. Evidence-Based Beta-Blockers

• Use only one of the three beta-blockers with proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol—each provides at least 20% mortality reduction. 3, 1
• Start carvedilol at 3.125 mg twice daily (target: 25-50 mg twice daily), metoprolol succinate at 12.5-25 mg daily (target: 200 mg daily), or bisoprolol at 1.25 mg daily (target: 10 mg daily). 3, 2
• Carvedilol is preferred if refractory hypertension coexists due to its combined α1-β1-β2-blocking properties. 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Start spironolactone at 12.5-25 mg daily (target: 25-50 mg daily) or eplerenone at 25 mg daily (target: 50 mg daily)—both provide at least 20% mortality reduction. 1
• Eplerenone is preferred in men concerned about gynecomastia, as spironolactone carries a 5.7% higher rate of this adverse effect. 1
• Initiate only if serum potassium <5.0 mmol/L, creatinine <2.5 mg/dL, and eGFR >30 mL/min. 4

4. SGLT2 Inhibitors

• Start dapagliflozin 10 mg daily or empagliflozin 10 mg daily—no dose titration required—providing significant mortality benefits with treatment effects occurring within weeks. 1
• SGLT2 inhibitors have unique advantages: no blood pressure, heart rate, or potassium effects, making them ideal for immediate initiation even in patients with borderline low blood pressure. 1, 2
• Safe in moderate kidney dysfunction (eGFR ≥30 mL/min/1.73 m² for empagliflozin; ≥20 mL/min/1.73 m² for dapagliflozin). 1

Simultaneous Initiation Protocol (Preferred Strategy)

Start all four medication classes simultaneously at low doses rather than sequential initiation—this approach addresses the massive treatment gap where less than 25% of eligible patients receive all medications concurrently and only 1% reach target doses. 1

• Day 1 after hemodynamic stabilization: Initiate SGLT2 inhibitor + beta-blocker (minimal blood pressure effects). 2
• Within 24-48 hours: Add ARNI (or ACE inhibitor) + MRA if blood pressure and renal function permit. 1
• Uptitrate every 1-2 weeks until target doses are achieved, checking blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment. 1

Diuretic Management (Symptom Relief Only)

• Loop diuretics are purely for symptom control and do not improve prognosis—use at the lowest effective dose to relieve fluid retention. 4, 2
• In hospitalized patients, initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrated based on urine output and congestion symptoms. 1
• Monitor closely for volume depletion, electrolyte disturbances, and worsening renal function when increasing diuretic intensity. 4

Secondary/Adjunctive Therapies (Specific Indications)

Ivabradine

• Add ivabradine 5 mg twice daily (target: 7.5 mg twice daily) only if heart rate remains >70 bpm despite maximally tolerated beta-blocker doses and patient is in sinus rhythm with NYHA class II-III symptoms. 3
• Critical caveat: Only 25% of participants in the ivabradine trial were on optimal beta-blocker doses—beta-blocker uptitration to target must precede ivabradine. 1

Hydralazine/Isosorbide Dinitrate

• Add hydralazine 37.5 mg three times daily + isosorbide dinitrate 20 mg three times daily (target: 75 mg/40 mg three times daily) specifically for self-identified Black patients with NYHA class III-IV symptoms on top of quadruple therapy. 1

Vericiguat

• Consider vericiguat 2.5 mg daily (target: 10 mg daily) in high-risk patients with recent worsening heart failure despite optimal GDMT. 5

Digoxin

• Digoxin 0.125-0.25 mg daily may be added for persistent symptoms despite optimal GDMT, though it does not reduce mortality. 6

Managing Common Barriers to Uptitration

Hypotension

• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg—asymptomatic or mildly symptomatic low blood pressure should not prompt GDMT reduction. 1
• If systolic BP <90 mmHg, prioritize medications in this order: SGLT2 inhibitor and MRA first (minimal BP impact), then selective β1-blocker, then low-dose ACE inhibitor/ARB or very low-dose ARNI. 1

Hyperkalemia

• Modest potassium elevation (5.0-5.5 mmol/L) is acceptable—reduce MRA dose or add potassium binder (patiromer, sodium zirconium cyclosilicate) rather than discontinuing. 1
• Never use ACE inhibitor + ARB + MRA triple combination due to severe hyperkalemia and renal dysfunction risk. 2

Worsening Renal Function

• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt ACE inhibitor/ARB/ARNI discontinuation. 1
• Temporary dose reduction is acceptable if substantial renal deterioration occurs, but aggressive attempts to restore target doses should follow. 1

Fatigue and Weakness

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT. 1

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated—in-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting. 1
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion. 1

Improved Ejection Fraction

• Patients whose EF improves to >40% should continue their HFrEF treatment regimen—discontinuation may lead to clinical deterioration. 1

Elderly Patients (≥65 years)

• All four medication classes remain indicated, though more frequent monitoring is needed during uptitration. 3, 1

Chronic Kidney Disease

• GDMT remains indicated with closer monitoring; SGLT2 inhibitors are safe down to eGFR 20-30 mL/min/1.73 m² depending on agent. 1

Device Therapies (After Optimal Medical Therapy)

• Implantable cardioverter-defibrillator (ICD): Indicated for primary prevention in patients with ischemic cardiomyopathy, LVEF ≤35%, and NYHA class II-III symptoms after ≥3 months of optimal GDMT. 1
• Cardiac resynchronization therapy (CRT): Recommended for patients with LVEF ≤35%, sinus rhythm, QRS duration ≥150 ms (especially left bundle branch block), and NYHA class II-IV symptoms despite optimal GDMT. 1

Implementation Strategies to Improve Adherence

• Nurse-led titration programs reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92). 1
• Pharmacist involvement improves GDMT adherence and dosing. 1
• Structured patient-education programs (printed materials, mobile applications, video education) significantly improve adherence and are associated with reductions in mortality and hospitalizations. 1
• Early follow-up within 7-14 days after medication changes with monitoring of volume status, blood pressure, renal function, and electrolytes. 1

Critical Contraindications and Medications to Avoid

• Never combine ACE inhibitor with ARNI (angioedema risk). 2
• Avoid non-dihydropyridine calcium channel blockers (diltiazem, verapamil), moxonidine, and alpha-adrenergic blockers—they may worsen heart failure outcomes. 1
• Do not use other beta-blockers (atenolol, propranolol, etc.) that lack proven mortality benefit in HFrEF—switch to carvedilol, metoprolol succinate, or bisoprolol. 2