What guideline‑directed medical therapy should be initiated for an adult with symptomatic reduced‑ejection‑fraction heart failure?

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

Initiate all four foundational medication classes simultaneously at low doses—ARNI (sacubitril/valsartan preferred), beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), mineralocorticoid receptor antagonist (spironolactone or eplerenone), and SGLT2 inhibitor (dapagliflozin or empagliflozin)—then uptitrate every 1-2 weeks to target doses regardless of symptom severity. 1, 2, 3

The Four Pillars of GDMT

1. Renin-Angiotensin System Inhibition: ARNI Preferred

• Start sacubitril/valsartan 24/26 mg twice daily, target 97/103 mg twice daily, which provides at least 20% mortality reduction superior to ACE inhibitors or ARBs. 2, 4, 5
• If switching from an ACE inhibitor, observe a strict 36-hour washout period to avoid angioedema. 1, 5
• 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), which provide 5-16% mortality reduction. 4

2. Beta-Blockers: Only Three Evidence-Based Options

• Use only carvedilol, metoprolol succinate, or bisoprolol—each provides at least 20% mortality reduction and reduces sudden cardiac death. 1, 2, 3, 4
• Dosing targets: carvedilol 3.125 mg twice daily → 25-50 mg twice daily; metoprolol succinate 12.5-25 mg daily → 200 mg daily; bisoprolol 1.25 mg daily → 10 mg daily. 4
• Do not use metoprolol tartrate, atenolol, or other non-evidence-based beta-blockers. 3

3. Mineralocorticoid Receptor Antagonists

• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily, targeting spironolactone 25-50 mg daily or eplerenone 50 mg daily, which provide at least 20% mortality reduction. 2, 3, 4
• Eplerenone avoids the 5.7% higher rate of gynecomastia seen with spironolactone. 4

4. SGLT2 Inhibitors: Newest Class with Rapid Benefit

• Start dapagliflozin 10 mg daily or empagliflozin 10 mg daily—no titration required, benefits occur within weeks, independent of background therapy. 1, 2, 3, 4, 6
• These agents have minimal blood pressure impact (average 1.5 mmHg SBP reduction), no heart rate or potassium effects, and are safe with eGFR ≥20 mL/min/1.73 m² for dapagliflozin and ≥30 mL/min/1.73 m² for empagliflozin. 4, 6

Combined Therapy Impact

• Quadruple therapy reduces 2-year mortality by approximately 73% compared to no treatment and extends life expectancy by approximately 6 years compared to traditional dual therapy (ACE inhibitor plus beta-blocker). 3, 4

Initiation Strategy: Simultaneous, Not Sequential

• Start all four medication classes simultaneously at low doses after hemodynamic stabilization, rather than waiting to achieve target dosing of one before initiating the next. 1, 2, 3, 4
• This approach addresses the massive treatment gap where less than 25% of eligible patients receive all four agents concurrently and only 1% reach target doses. 2, 4
• Uptitrate every 1-2 weeks to target doses shown effective in trials, regardless of symptom severity. 1, 2

Monitoring During Uptitration

• Check blood pressure, renal function (creatinine/eGFR), and electrolytes (potassium) 1-2 weeks after each dose increment. 2, 3, 4
• More frequent monitoring is needed in elderly patients (≥65 years) and those with chronic kidney disease. 3, 4
• Modest creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB. 4

Managing Low Blood Pressure During Initiation

• Asymptomatic or mildly symptomatic systolic BP 80-100 mmHg is not a reason to reduce or stop GDMT when perfusion is adequate. 2, 4
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (e.g., syncope, altered mental status, acute kidney injury). 2, 4

Medication Prioritization in Low BP Patients

• Start SGLT2 inhibitor and MRA first (minimal BP impact), then add beta-blocker if heart rate >60 bpm, finally add ARNI/ACE inhibitor/ARB. 2, 4
• Discontinue non-essential medications that lower BP (e.g., alpha-blockers for benign prostatic hyperplasia). 4

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated. 3, 4
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion; in-hospital initiation substantially improves post-discharge medication use. 4
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrated based on urine output and congestion. 3

Patients with Improved Ejection Fraction

• Continue all HFrEF medications even if EF improves to >40%, as discontinuation may lead to clinical deterioration. 1, 4

Elderly Patients (≥65 Years)

• All four medication classes remain indicated, but perform more frequent monitoring of BP, renal function, and electrolytes during uptitration. 4, 6

Additional Therapies

Loop Diuretics

• Add loop diuretics only if fluid overload is present—they provide symptom relief but no mortality benefit. 3, 4

Ivabradine

• Add ivabradine 5 mg twice daily (target 7.5 mg twice daily) only if: patient is in sinus rhythm with NYHA class II-III symptoms, resting heart rate >70 bpm despite maximally tolerated beta-blocker therapy. 4

Hydralazine-Isosorbide Dinitrate

• Add to quadruple therapy only for self-identified Black patients with NYHA class III-IV symptoms. 4

Implementation Strategies to Improve Adherence

• Multidisciplinary care teams (including pharmacists and nurses) improve GDMT titration, reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92), and reduce HF hospitalizations. 2, 4
• Early follow-up within 7-14 days after medication changes, monitoring volume status, BP, renal function, and electrolytes. 4
• Nurse-led titration programs and pharmacist involvement significantly improve GDMT adherence and dosing. 4

Common Pitfalls to Avoid

• Do not use non-evidence-based beta-blockers (e.g., metoprolol tartrate, atenolol). 3
• Do not withhold GDMT for asymptomatic hypotension when perfusion is adequate. 2, 4
• Do not discontinue GDMT for modest creatinine increases (<30% above baseline). 4
• Do not wait to achieve target dosing of one medication before starting the next—simultaneous initiation is superior. 2, 4
• Do not use calcium channel blockers (non-dihydropyridine), moxonidine, or alpha-adrenergic blockers, as they may worsen HF outcomes. 4