What is the goal-directed therapy for a patient with heart failure (HF), specifically for patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF)?

Goal-Directed Medical Therapy for Heart Failure

HFrEF: Quadruple Therapy is the Foundation

All patients with HFrEF should be initiated on quadruple guideline-directed medical therapy (GDMT) simultaneously at low doses, then rapidly uptitrated to target doses within 2 months, as this approach reduces mortality by approximately 73% over 2 years compared to no treatment. 1

The Four Foundational Medication Classes for HFrEF

Start all four classes simultaneously—do not wait to achieve target dosing of one medication before initiating the next. 1

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - PREFERRED

   • Sacubitril/valsartan is first-line over ACE inhibitors or ARBs, providing ≥20% mortality reduction versus 5-16% for ACEi/ARBs 1
   • Target dose: 97/103 mg twice daily 1
   • Critical safety requirement: 36-hour washout period when switching from ACE inhibitor to ARNI to avoid angioedema 1
   • If ARNI not feasible, use ACE inhibitor (e.g., lisinopril up to 35 mg daily) or ARB 1, 2

2. Beta-Blockers

   • Use carvedilol, metoprolol succinate, or bisoprolol—these provide ≥20% reduction in mortality risk 1
   • Carvedilol is preferred if refractory hypertension is present due to combined α1-β1-β2-blocking properties 1
   • If beta-blockers are not hemodynamically tolerated, ivabradine may be considered as an alternative for heart rate control 1, 3

3. Mineralocorticoid Receptor Antagonists (MRAs)

   • Spironolactone or eplerenone provide ≥20% reduction in mortality risk 1
   • Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) 1
   • Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 1
   • Monitor potassium and creatinine closely 1

4. SGLT2 Inhibitors

   • Dapagliflozin or empagliflozin have significant mortality benefits 1
   • Unique advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; treatment benefits occur within weeks 1
   • Safe in moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) 1
   • Should be initiated immediately—ideal for patients with low blood pressure or borderline hemodynamics 1

Aggressive Uptitration Strategy

Use a forced-titration approach with medication adjustments every 1-2 weeks until target doses are achieved, targeting completion within 2 months of initiation. 1, 2

• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1
• Asymptomatic or mildly symptomatic low blood pressure should not be a reason for GDMT reduction or cessation 1

Special Medication Prioritization for Low Blood Pressure

For patients with systolic blood pressure <90 mmHg but adequate perfusion, prioritize medications in this order: 1

1. SGLT2 inhibitors and MRAs first (minimal BP impact)
2. Selective β₁ receptor blockers
3. Low-dose ACEi/ARB or very low-dose ARNI

Additional Therapies for Specific Populations

• For self-identified Black patients with NYHA Class III-IV symptoms: add hydralazine/isosorbide dinitrate to quadruple therapy 1
• For patients with QRS duration >130-150 ms despite optimal medical therapy: consider cardiac resynchronization therapy (CRT) 2

Volume Management

• Add loop diuretics only if fluid overload is present (peripheral edema, elevated JVP, rapid weight gain >2 kg in 3 days, pulmonary congestion) 1, 2
• Initial IV dose should equal or exceed chronic oral daily dose 1
• Avoid excessive diuresis before starting ACE inhibitors/ARNI, as this can cause hypotension and renal dysfunction 2
• For diuretic resistance, consider combination therapy (loop + thiazide) 1

Critical Implementation Principles

Hospitalized patients should have GDMT initiated after ≥24 hours of stabilization with adequate organ perfusion—in-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting. 1

Continue GDMT in hospitalized patients except when hemodynamically unstable or contraindicated. 1, 2

Medications to AVOID in HFrEF

• Non-dihydropyridine calcium channel blockers, moxonidine, and alpha-adrenergic blockers may increase risk of worsening heart failure 1

Critical Pitfall to Avoid

Never discontinue GDMT even if ejection fraction improves—patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen indefinitely, as discontinuation leads to clinical deterioration. 1, 2

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HFpEF: SGLT2 Inhibitors are First-Line

SGLT2 inhibitors are the first-line disease-modifying therapy for HFpEF (Class 2a recommendation), combined with loop diuretics for symptom relief from congestion. 4

Primary Goal in HFpEF

The primary goal is reducing heart failure hospitalizations and cardiovascular mortality while improving quality of life, as HFpEF has primarily reduction in hospitalizations rather than mortality benefits 1, 4

Evidence-Based Pharmacological Therapy for HFpEF

1. SGLT2 Inhibitors (STRONGEST RECOMMENDATION - Class 2a)

   • Dapagliflozin reduces the composite endpoint of worsening heart failure and cardiovascular death by 18% (HR 0.82) and heart failure hospitalizations by 23% (HR 0.77) 4
   • Empagliflozin reduces hospitalization for heart failure and cardiovascular death by 21% (HR 0.79) 4
   • Based on DELIVER and EMPEROR-PRESERVED trials 1

2. Loop Diuretics

   • Use at the lowest effective dose to relieve congestion and manage volume overload 4
   • Titrate based on symptoms and volume status 4

3. Mineralocorticoid Receptor Antagonists (Weaker Recommendation - Class 2b)

   • Consider spironolactone for HFpEF patients with LVEF in the lower preserved range (40-50%), particularly those who can tolerate monitoring 4
   • Reduces heart failure hospitalizations (HR 0.83) based on TOPCAT trial 1, 4
   • Requires regular assessment of renal function and electrolytes 4

4. Sacubitril/Valsartan (Selected Patients)

   • May be considered for selected HFpEF patients, especially women and those with LVEF 45-57% 4
   • Subgroup analysis showed benefit in women (rate ratio 0.78) and those with LVEF 45-57% (rate ratio 0.73) 4

Comorbidity Management is Critical in HFpEF

Hypertension control is a cornerstone of HFpEF management (Class I recommendation). 1

Treatment of atrial fibrillation for symptom management (Class 2a recommendation). 1

Use a phenotype-directed approach focusing on comorbidity management (hypertension, diabetes, obesity, atrial fibrillation) alongside specific HF therapies 1

Non-Pharmacological Management

• Supervised exercise training programs improve functional capacity and quality of life 4
• Multidisciplinary heart failure programs should be offered to all HFpEF patients 4
• Cardiac rehabilitation is recommended despite less robust evidence than in HFrEF 4

Monitoring in HFpEF

• Regular assessment of volume status, renal function, and electrolytes 4
• Monitor symptoms and functional capacity to guide treatment adjustments 4
• Minimum follow-up every 6 months for stable HFpEF patients, with increased frequency for clinical instability 4

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Key Differences Between HFrEF and HFpEF GDMT

HFrEF has strong mortality benefit with all four medication classes (Class I recommendations), while HFpEF has primarily reduction in hospitalizations rather than mortality, with SGLT2i having the strongest evidence (Class 2a). 1

Transitioning a patient from traditional dual therapy (ACEi and beta-blocker) to quadruple therapy can extend life expectancy by approximately 6 years in HFrEF. 1

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Implementation Strategies to Overcome Barriers

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

Early follow-up within 7-14 days after medication adjustments is recommended, with monitoring for volume status, blood pressure, renal function, electrolytes, and symptoms 1, 2

Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization. 1