What is the guideline‑directed treatment plan, including medications and device therapy, for an adult patient with heart failure with reduced ejection fraction?

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

All adult patients with HFrEF (EF ≤40%) should be initiated 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 every 1-2 weeks to target doses, as this approach reduces 2-year mortality by approximately 73% compared to no treatment. 1

Core Pharmacologic Components

Renin-Angiotensin System Inhibition

• Sacubitril/valsartan (ARNI) is the preferred agent over ACE inhibitors or ARBs, providing at least 20% mortality reduction versus the 5-16% reduction seen with ACE-I/ARB alone 1
• 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 unavailable, initiate an ACE inhibitor (lisinopril 10 mg daily, target 40 mg daily) or ARB (losartan 50 mg daily, target 150 mg daily) 1

Beta-Blockers

• Use one of three evidence-based beta-blockers: 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), or bisoprolol (start 1.25 mg daily, target 10 mg daily) 1
• Each provides at least 20% mortality reduction and lowers sudden cardiac death risk 1
• If refractory hypertension is present, carvedilol is preferred due to its combined α1-β1-β2-blocking properties 1

Mineralocorticoid Receptor Antagonists

• Initiate spironolactone (12.5-25 mg daily, target 25-50 mg daily) or eplerenone (25 mg daily, target 50 mg daily) 2, 1
• Both provide at least 20% mortality reduction 1
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 1

SGLT2 Inhibitors

• Start dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately after stabilization—no titration required 1
• These agents have unique advantages: no blood pressure, heart rate, or potassium effects, and treatment benefits occur within weeks of initiation, independent of background therapy 1
• Safe in moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 1

Loop Diuretics (Symptom Management Only)

• Add loop diuretics only if fluid overload is present 2, 1
• In hospitalized patients, initial IV dose should equal or exceed chronic oral daily dose, then titrate based on urine output and congestion symptoms 1

Initiation Strategy: Simultaneous vs Sequential

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

Rapid Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved, using the forced-titration approach from landmark trials 1, 3
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1
• More frequent monitoring is needed in elderly patients (≥65 years) and those with chronic kidney disease 1

Managing Common Barriers to Optimization

Low Blood Pressure

• Patients with adequate organ perfusion can tolerate systolic BP 80-100 mmHg 2, 1
• Asymptomatic or mildly symptomatic low blood pressure should not be a reason for GDMT reduction or cessation 1
• If systolic BP <90 mmHg but perfusion is adequate, prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then selective β₁ receptor blockers, then low-dose ACE-I/ARB or very low-dose ARNI 1

Renal Function Changes

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

Hyperkalemia

• Monitor potassium closely when initiating or uptitrating MRAs 2
• Do not allow modest electrolyte changes to prevent uptitration if clinically stable 1

Special Clinical Scenarios

Hospitalized Patients

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

Heart Rate Control

• If beta-blockers are not hemodynamically tolerated, ivabradine may be considered as an alternative for heart rate control 1
• Add ivabradine (5 mg twice daily, target 7.5 mg twice daily) only when a patient in sinus rhythm with NYHA class II-III symptoms has resting heart rate >70 bpm despite maximally tolerated beta-blocker therapy 1
• 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 1

Self-Identified Black Patients with Advanced Symptoms

• For patients with NYHA Class III-IV symptoms, add hydralazine/isosorbide dinitrate to quadruple therapy 1

Improved Ejection Fraction

• Continue HFrEF medications even if ejection fraction improves to >40%, as discontinuation may lead to clinical deterioration 1

Device Therapy Considerations

Cardiac Resynchronization Therapy (CRT)

• CRT is recommended for patients in sinus rhythm with LVEF ≤35%, QRS duration ≥150 ms, and left bundle branch block morphology who remain symptomatic despite optimal medical therapy 2, 1

Implantable Cardioverter-Defibrillators (ICDs)

• ICDs are indicated for patients with ischemic cardiomyopathy and mild symptoms after they have received Class I pharmacologic therapy for an appropriate duration 1

Follow-Up and Monitoring

• Schedule early follow-up within 7-14 days after medication adjustments 1, 3
• Monitor volume status, blood pressure, renal function, electrolytes, and symptoms of worsening heart failure at each visit 1
• Refer newly diagnosed HFrEF patients to heart failure specialty care to maximize GDMT optimization 1

Implementation Strategies

• 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
• Use digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits to increase GDMT prescription 1
• Structured patient-education programs (printed materials, mobile applications, video education) significantly improve adherence and are associated with reductions in mortality and hospitalizations 1

Critical Pitfalls to Avoid

• Do not prematurely discontinue GDMT—temporary symptoms of fatigue and weakness with dose increases usually resolve within days 1
• Do not overreact to laboratory changes; modest creatinine elevation (up to 30% above baseline) is acceptable 1
• Do not use non-dihydropyridine calcium channel blockers, moxonidine, or alpha-adrenergic blockers in HFrEF patients, as they may increase the risk of worsening heart failure 1
• Avoid excessive diuresis, as it may worsen hypotension 1