What is the guideline‑directed medical therapy for a typical adult with heart failure with reduced ejection fraction, including recommended medications, doses, and lifestyle measures?

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

All patients with HFrEF (LVEF ≤40%) should receive simultaneous initiation of four foundational medication classes—ARNI (sacubitril/valsartan), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—at low doses immediately after hemodynamic stabilization, with rapid uptitration every 1-2 weeks to target doses. 1

Core Pharmacologic Regimen

The Four Pillars of HFrEF Therapy

Renin-Angiotensin-Neprilysin Inhibitor (ARNI)

• Sacubitril/valsartan is the preferred first-line agent, providing ≥20% mortality reduction compared to 5-16% with ACE inhibitors or ARBs alone 1
• Start at 24/26 mg or 49/51 mg twice daily, uptitrate to target dose of 97/103 mg twice daily 1
• Observe a strict 36-hour washout period when switching from an ACE inhibitor to avoid angioedema 1
• If ARNI is not tolerated or unavailable, use ACE inhibitor (lisinopril 10 mg daily, target 40 mg daily) or ARB (losartan 50 mg daily, target 150 mg daily) 1

Beta-Blockers

• Use only the three evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol—each provides ≥20% mortality reduction 1
• Dosing regimens 1:
  • 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
• Choose carvedilol if refractory hypertension is present due to combined α1-β1-β2-blocking properties 1

Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone provide ≥20% mortality reduction 1
• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily, uptitrate to target doses 2
• Use eplerenone to avoid the 5.7% higher rate of gynecomastia seen with spironolactone 1
• Monitor potassium and creatinine closely; modest creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation 2, 1

SGLT2 Inhibitors

• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily—no titration required 1
• Unique advantages: no blood pressure, heart rate, or potassium effects; treatment benefits occur within weeks of initiation 1
• Safe in moderate kidney dysfunction (eGFR ≥30 mL/min/1.73 m² for empagliflozin, ≥20 mL/min/1.73 m² for dapagliflozin) 1
• 0.9% higher rate of genital infection is the primary adverse effect 1

Combined Mortality Benefit

Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment, and transitioning from traditional dual therapy to quadruple therapy extends life expectancy by approximately 6 years 1

Initiation Strategy

Simultaneous vs Sequential Approach

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

Rapid Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved, typically within 2 months of initiation 1
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 2, 1
• More frequent monitoring is needed in elderly patients (≥65 years) and those with chronic kidney disease 1

In-Hospital Initiation

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

Special Clinical Scenarios

Low Blood Pressure (SBP ~90 mmHg)

Prioritize medications in this specific order 1:

1. Start SGLT2 inhibitor and MRA first—these have minimal blood pressure impact 1
2. Add beta-blocker only if resting heart rate >60 bpm 1
3. Add ARNI (or ACE-I/ARB) last 1

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 1. Do not discontinue any GDMT component while SBP remains >80 mmHg and perfusion is sufficient 1.

Improved Ejection Fraction

Patients whose EF improves from HFrEF to >40% must continue all four HFrEF medications at target doses indefinitely—discontinuation leads to clinical deterioration 1, 3.

Self-Identified Black Patients with NYHA Class III-IV

Add hydralazine/isosorbide dinitrate to quadruple therapy 1.

Adjunctive Therapies

Loop Diuretics

Use only for relief of volume-overload symptoms (peripheral edema, elevated JVP, pulmonary congestion) 1. Initial IV dose should equal or exceed chronic oral daily dose, titrated based on urine output and congestion 1.

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 1

Beta-blocker uptitration to target doses must precede ivabradine; only 25% of participants in the ivabradine trial were on optimal beta-blocker doses 1.

Cardiac Resynchronization Therapy (CRT)

Recommended only for patients with markedly prolonged QRS duration (>130-150 ms) despite optimal medical therapy 1.

Implantable Cardioverter-Defibrillators (ICDs)

Indicated for patients with ischemic cardiomyopathy and mild symptoms after they have received Class I pharmacologic therapy for an appropriate duration 1.

Monitoring and Follow-Up

Structured Schedule

• Week 1-2: Initial follow-up after GDMT initiation 1
• Every 1-2 weeks: Uptitration visits until target doses achieved 1
• Early follow-up within 7-14 days after medication changes to monitor volume status, blood pressure, renal function, and electrolytes 1

Laboratory Monitoring

• Modest creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation of ACE-I/ARB/ARNI 2, 1
• Monitor potassium closely with MRAs; temporary dose reductions should be followed by aggressive attempts to restore target doses 2

Critical Pitfalls to Avoid

Never discontinue GDMT even if ejection fraction improves—this leads to clinical deterioration 1, 3

Do not withhold GDMT for asymptomatic hypotension when perfusion is adequate; patients can safely tolerate SBP 80-100 mmHg 1

Avoid premature discontinuation due to temporary symptoms—fatigue and weakness with dose increases usually resolve within days 1

Do not overreact to laboratory changes—modest creatinine elevation is acceptable in patients with adequate perfusion 1

Never use non-dihydropyridine calcium channel blockers, moxonidine, or alpha-adrenergic blockers in HFrEF—they may increase the risk of worsening heart failure 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. Digital solutions (best practice advisories, EHR-based interventions, telehealth visits) increase GDMT prescription rates 1.

Structured patient-education programs (printed materials, mobile applications, video education) significantly improve adherence and are associated with reductions in mortality and hospitalizations 1.

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)

SGLT2 inhibitors receive a Class 2a recommendation and should be initiated first in all HFmrEF patients 3

Beta-blockers, RAS inhibitors, and MRAs carry Class 2b (weak) recommendations 3:

• For LVEF 41-44%: strongly consider adding all three classes using the same approach as HFrEF 3
• For LVEF 45-49%: individualize based on symptoms, comorbidities, and tolerability 3

Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF ≥50%)

SGLT2 inhibitors are the strongest recommendation (Class 2a) based on DELIVER and EMPEROR-PRESERVED trials showing reduction in HF hospitalizations and cardiovascular death 2, 1

Strict systolic and diastolic blood pressure control is a Class I recommendation 1

MRAs have a weaker recommendation (Class 2b) based on TOPCAT trial data 2, 1

Treat atrial fibrillation for symptom management (Class 2a) 2