What are the optimal treatment strategies for heart failure?

Optimal Treatment Strategies for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF should receive quadruple foundational therapy consisting of an ACE inhibitor (or ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor, initiated rapidly and titrated to target doses using forced-titration strategies proven in landmark trials. 1, 2

Core Pharmacological Therapy Algorithm

Step 1: Immediate Initiation (Within Days of Diagnosis)

Start all four foundational drug classes simultaneously or in rapid sequence:

• ACE Inhibitor (or ARNI if already on stable ACE inhibitor): Reduces mortality by 10-40% depending on severity 1, 3

  • Start low dose and titrate to target doses proven in trials 4
  • Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 4
  • Avoid excessive diuresis before starting; reduce or withhold diuretics for 24 hours if possible 4
  • Avoid NSAIDs during therapy 4

• Beta-blocker (bisoprolol, carvedilol, or metoprolol succinate): Reduces mortality by 35% and sudden death by 40% 3

  • Use only evidence-based agents (bisoprolol, carvedilol, metoprolol succinate) 5, 3
  • Titrate to target doses used in MERIT-HF and similar trials 5
  • Can be initiated even in NYHA Class IV after stabilization 1

• Mineralocorticoid Receptor Antagonist (spironolactone ≤25-50 mg daily): For NYHA Class II-IV 1, 6

  • Mandatory when LVEF <35% or symptoms persist despite ACE inhibitor and beta-blocker 1
  • Requires preserved renal function and normal potassium 1
  • Avoid potassium-sparing diuretics during initiation 4

• SGLT2 Inhibitor: First-line therapy with mortality and hospitalization benefits 2

  • Initiate regardless of diabetes status 2

Step 2: Consider ARNI Substitution

Replace ACE inhibitor with sacubitril/valsartan (ARNI) in patients with persistent symptoms (NYHA II-IV) despite optimal medical therapy: 1, 7

• Provides superior mortality reduction compared to ACE inhibitors alone 1
• Requires 36-hour washout period from ACE inhibitor 1
• Contraindicated if history of angioedema with ACE inhibitors 1

Step 3: Diuretic Management

Add loop diuretics only for symptomatic fluid overload (pulmonary congestion, peripheral edema): 4, 3

• Loop diuretics superior to thiazides for heart failure 7
• Use cautiously to avoid excessive preload reduction that decreases stroke volume 1, 6
• For diuretic resistance, combine loop diuretic with thiazide 1
• Titrate to achieve euvolemia, then reduce to lowest effective dose 4

Step 4: Additional Therapies for Persistent Symptoms

If symptoms persist despite quadruple therapy at target doses:

• Digoxin: For NYHA Class III-IV with large hearts and systolic dysfunction 1, 3

  • Does not reduce mortality but improves symptoms and reduces hospitalizations 3
  • Essential for atrial fibrillation with rapid ventricular rate 1, 3

• Hydralazine plus nitrate: For ACE inhibitor intolerance due to hypotension or renal insufficiency 1

  • Class IIa recommendation when ACE inhibitor cannot be used 1

• Ivabradine: If heart rate >70 bpm despite maximally tolerated beta-blocker 7

Critical Forced-Titration Strategy

The key to optimal outcomes is not just prescribing these medications, but achieving target doses through forced-titration protocols used in landmark trials: 1

• Subtarget doses prescribed outside forced-titration strategies lack evidence for efficacy 1
• Patients receiving target doses after demonstrating intolerance to higher doses during forced-titration attempts still achieve guideline-directed therapy 1
• Simply prescribing low doses without systematic up-titration attempts does not constitute evidence-based care 1

Specific Clinical Scenarios

NYHA Class II (Mild Heart Failure)

• ACE inhibitor + beta-blocker + MRA + SGLT2 inhibitor titrated to target doses 4
• Diuretics only during episodes of fluid overload 4

NYHA Class III-IV (Moderate to Severe Heart Failure)

• All foundational therapies plus diuretics 4
• Add spironolactone (mandatory) 1, 6
• Consider digoxin 1
• Evaluate for advanced therapies if refractory 1

Stage D (Refractory End-Stage Heart Failure)

• Confirm diagnosis accuracy and optimize all conventional therapies first 1
• Meticulous fluid management is critical 1
• Consider mechanical circulatory support, continuous intravenous inotropes, cardiac transplantation, or hospice 1
• Avoid long-term intermittent intravenous positive inotropic therapy (Class III recommendation - harmful) 1

Contraindicated or Harmful Therapies

Never use the following in heart failure: 1, 4

• Calcium channel blockers as heart failure treatment (Class III) 1
• Routine inotropic therapy (increases mortality) 4
• Nutritional supplements (coenzyme Q10, carnitine, taurine) or hormonal therapies (growth hormone, thyroid hormone) 1
• Dynamic cardiomyoplasty 1
• ARB before beta-blocker in patients already on ACE inhibitor (Class III) 1

Common Pitfalls to Avoid

• Therapeutic inertia: Failure to initiate all four foundational therapies rapidly is the most common error 1, 2
• Underdosing: Prescribing subtarget doses without attempting forced-titration 1
• Sequential rather than simultaneous initiation: Delays in adding subsequent therapies 1
• Excessive diuresis: Over-diuresis before ACE inhibitor initiation causes hypotension and renal dysfunction 4
• Monitoring failures: Not checking renal function and electrolytes after dose changes 4

Monitoring and Reassessment

Reassess after initiating foundational therapies: 2

• Evaluate symptoms, health status, and left ventricular function 2
• Refer to heart failure specialist if persistent advanced symptoms or worsening despite optimal therapy 2
• Monitor BNP/NT-proBNP levels to guide therapy adjustments 6

Non-Pharmacological Management

Essential lifestyle modifications: 4

• Explain heart failure pathophysiology and self-management 4
• Daily physical and leisure activities to prevent deconditioning 4
• Sodium restriction in severe heart failure 4
• Avoid excessive fluid intake in severe heart failure 4
• Avoid excessive alcohol 4
• Exercise training programs for stable NYHA II-III patients 1, 4