What is the initial treatment regimen for patients with heart failure, specifically those with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)?

Initial Treatment Regimen for Heart Failure

Heart Failure with Reduced Ejection Fraction (HFrEF)

For patients with HFrEF, initiate four foundational medications simultaneously at low doses (the "fantastic four"): an ARNI (sacubitril/valsartan), a beta-blocker, an MRA (mineralocorticoid receptor antagonist), and an SGLT2 inhibitor, then titrate upward as tolerated. 1, 2

Step 1: Foundational Quadruple Therapy

Start all four medications together without waiting to reach target doses of one before initiating another 1:

• ARNI (Sacubitril/Valsartan): Preferred over ACE inhibitors or ARBs as first-line therapy for NYHA class II-III symptoms to reduce mortality and HF hospitalization 1, 2

  • If ARNI is not feasible, use an ACE inhibitor as second choice 1
  • ARBs are reserved only for patients intolerant to ACE inhibitors due to cough or angioedema 1

• Beta-Blocker: Use bisoprolol, carvedilol, or sustained-release metoprolol succinate to reduce mortality and hospitalization 1, 2

  • Start at low doses and titrate to target over 6-12 weeks 2

• MRA (Spironolactone or Eplerenone): Add for patients with NYHA class II-IV who remain symptomatic despite ACE inhibitor/ARNI and beta-blocker 1, 2

  • Monitor serum creatinine (≤2.5 mg/dL in men, ≤2.0 mg/dL in women) and potassium (<5.0 mEq/L) 3, 4

• SGLT2 Inhibitor (Dapagliflozin or Empagliflozin): Reduces HF hospitalization and cardiovascular mortality independent of diabetes status 2, 5

Step 2: Diuretics for Congestion

• Loop Diuretics: Use furosemide, bumetanide, or torasemide as needed to relieve breathlessness and edema in patients with fluid retention 1, 2
  • Titrate to achieve euvolemia ("dry weight") then reduce to lowest effective dose to avoid dehydration and renal dysfunction 1

Step 3: Additional Therapy for Specific Populations

• Hydralazine plus Isosorbide Dinitrate: Add for self-identified African American patients with NYHA class II-IV who remain symptomatic despite optimal therapy with ARNI/ACE inhibitor, beta-blocker, and MRA 1, 3

Step 4: Device Therapy

• ICD (Implantable Cardioverter-Defibrillator): Indicated for LVEF ≤35%, NYHA class II-III on optimal medical therapy for ≥3 months, with ischemic heart disease (>40 days post-MI) or dilated cardiomyopathy 1

• CRT (Cardiac Resynchronization Therapy): For LVEF ≤35%, NYHA class II-IV, sinus rhythm, QRS ≥150 ms with left bundle branch block morphology 1, 2

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Heart Failure with Preserved Ejection Fraction (HFpEF)

For patients with HFpEF, initiate an SGLT2 inhibitor as the primary disease-modifying therapy, combined with diuretics for congestion management and aggressive treatment of comorbidities. 1

Primary Disease-Modifying Therapy

• SGLT2 Inhibitor (Dapagliflozin or Empagliflozin): First-line therapy to reduce HF hospitalization and cardiovascular death 1
  • Dapagliflozin showed HR 0.82 for composite outcome of worsening HF and CV death in DELIVER trial 1
  • Empagliflozin showed HR 0.79 for hospitalization and CV death in EMPEROR-PRESERVED trial 1

Symptom Management

• Loop Diuretics: Use judiciously to reduce congestion and improve symptoms without causing excessive volume depletion 1
  • Monitor exercise tolerance as HFpEF patients are sensitive to preload reduction 1

Additional Therapies for Selected Patients

• MRA (Spironolactone): Consider for symptomatic patients, though benefit is modest (HR 0.89 in TOPCAT trial) 1

• ARNI (Sacubitril/Valsartan): May be considered, though PARAGON-HF showed borderline benefit (rate ratio 0.87, p=NS) 1

  • Greater benefit observed in patients with LVEF closer to 40% and women 1

• ARB (Candesartan): Alternative option, though CHARM-Preserved showed only borderline significance (HR 0.86, p=0.051) 1

Comorbidity Management

Aggressively treat underlying conditions that worsen HFpEF 1:

• Hypertension: Use stepped-care approach with GDMT agents 1
• Diabetes: SGLT2 inhibitors serve dual purpose 1
• Obesity: Weight loss improves symptoms and functional capacity 1
• Atrial Fibrillation: Rate control with beta-blockers or rate-limiting calcium channel blockers (verapamil) 1
• Obstructive Sleep Apnea: Screen and treat 1

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Critical Implementation Points

Titration Strategy

Increase medication doses to target over 6-12 weeks as tolerated, monitoring blood pressure, heart rate, renal function, and electrolytes at each step. 2

Medications to Avoid

• NSAIDs: Worsen renal function and counteract GDMT benefits 2
• Diltiazem or Verapamil in HFrEF: Increase risk of HF worsening (safe only in HFpEF) 1
• Triple Renin-Angiotensin System Blockade: Do not combine ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1
• Most Antiarrhythmics and Non-Dihydropyridine Calcium Channel Blockers in HFrEF: Increase mortality 4

Common Pitfalls

The most frequent errors are underutilization of GDMT, inadequate dose titration, and inappropriate medication discontinuation during temporary clinical worsening 2. Do not wait to achieve target doses of one medication before starting others—initiate all foundational therapies simultaneously at low doses 1.