What is the recommended approach for the long-term management of heart failure?

Long-Term Management of Heart Failure

All patients with heart failure with reduced ejection fraction (HFrEF) should receive quadruple therapy consisting of ACE inhibitors (or ARNI), beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, initiated simultaneously at low doses and titrated to target doses proven in clinical trials to reduce mortality. 1

Foundational Pharmacological Therapy for HFrEF

First-Line Quadruple Therapy

ACE Inhibitors (or ARNI)

• ACE inhibitors are the cornerstone of therapy and should be initiated in all patients with reduced left ventricular systolic function, even if asymptomatic 2
• Start with low doses (e.g., enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg daily) and titrate every 1-2 weeks to target doses proven effective in trials: enalapril 10-20 mg twice daily, lisinopril 20-35 mg daily 2
• Sacubitril/valsartan (ARNI) is superior to ACE inhibitors alone, reducing cardiovascular death and heart failure hospitalization, and should be considered as a replacement for ACE inhibitors in appropriate patients 1
• Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and then every 6 months 2
• If serum creatinine increases substantially or potassium exceeds 5.5 mmol/L, reduce dose or discontinue 2

Beta-Blockers

• Only three beta-blockers have proven mortality benefit: bisoprolol, carvedilol, and metoprolol succinate, which reduce all-cause mortality by 30% and cardiovascular death by 35% 3, 4
• Initiate only when patients are relatively stable without intravenous inotropic support or marked fluid retention 2, 4
• Start with very low doses (e.g., carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, bisoprolol 1.25 mg daily) and double every 1-2 weeks to target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 3, 4
• If worsening symptoms occur during titration, increase diuretics or ACE inhibitors first before reducing beta-blocker dose 4
• For hypotension during titration, reduce vasodilators rather than the beta-blocker 4

Mineralocorticoid Receptor Antagonists (MRA)

• Spironolactone improves survival and morbidity in advanced heart failure (NYHA III-IV) and should be added to ACE inhibitor and diuretic therapy 2
• Start with 25 mg daily only if serum potassium is less than 5.0 mmol/L and creatinine is less than 250 μmol/L (approximately 2.8 mg/dL) 4
• Check potassium and creatinine after 4-7 days; if potassium rises above 5.5 mmol/L, reduce dose by 50% or discontinue 2, 4
• Recheck electrolytes every 5-7 days until stable, then monitor regularly 2

SGLT2 Inhibitors

• SGLT2 inhibitors provide mortality benefit with minimal blood pressure effects and should be initiated early regardless of diabetes status 1
• These agents reduce cardiovascular death and heart failure hospitalization and represent the fourth pillar of modern HFrEF therapy 1, 4

Diuretic Therapy

Loop Diuretics or Thiazides

• Diuretics are essential for symptomatic relief when fluid overload manifests as pulmonary congestion or peripheral edema 2
• Always administer in combination with ACE inhibitors 2
• If glomerular filtration rate is less than 30 mL/min, avoid thiazides except when prescribed synergistically with loop diuretics 2
• For insufficient response: increase diuretic dose, combine loop diuretics with thiazides, administer loop diuretics twice daily, or add metolazone in severe cases with frequent creatinine and electrolyte monitoring 2

Additional Pharmacological Options

Digoxin

• In atrial fibrillation with any degree of symptomatic heart failure, digoxin slows ventricular rate and improves symptoms 2
• In sinus rhythm, digoxin improves clinical status in patients with persistent symptoms despite ACE inhibitor and diuretic treatment, but provides no mortality benefit 2, 3
• Usual dose is 0.25-0.375 mg daily if renal function is normal; reduce to 0.125-0.25 mg daily in elderly patients 2, 1
• Contraindications include bradycardia, second- or third-degree AV block, sick sinus syndrome, and electrolyte abnormalities (hypokalemia, hypercalcemia) 2, 4

Ivabradine

• Reserved for patients who remain symptomatic (NYHA II-III) despite maximally tolerated beta-blocker therapy, with LVEF ≤35%, sinus rhythm, and heart rate ≥70 bpm 3, 5
• Reduces hospitalization for worsening heart failure but does not reduce cardiovascular mortality 5
• Initiate at 5 mg twice daily and titrate to 7.5 mg twice daily to maintain resting heart rate between 50-60 bpm 5

Angiotensin II Receptor Blockers (ARBs)

• ARBs should be considered only in patients who cannot tolerate ACE inhibitors due to cough or angioedema 2
• It remains unclear whether ARBs are as effective as ACE inhibitors for mortality reduction 2
• When combined with ACE inhibitors, ARBs may improve symptoms and reduce hospitalizations, but avoid combining ACE inhibitors, ARBs, and MRAs due to increased risk of renal dysfunction and hyperkalemia 2, 4

Critical Dosing Principles

Target Doses Are Non-Negotiable

• Most patients in clinical practice receive starting doses indefinitely, but only target doses proven in clinical trials reduce mortality 2
• Physicians must titrate aggressively to target doses rather than accepting "medium-range" doses, as higher doses provide incremental mortality benefit 2
• For sacubitril/valsartan, fewer than 25% of patients in practice reach the target dose of 97/103 mg twice daily, compared to over 70% in the PARADIGM-HF trial 2
• The approach should mirror oncology: initiate therapy at target doses when possible and down-titrate only for intolerable adverse effects, as heart failure is more lethal than most cancers 2

Management of Heart Failure with Preserved Ejection Fraction (HFpEF)

SGLT2 Inhibitors as First-Line Therapy

• SGLT2 inhibitors are the cornerstone of HFpEF treatment, providing mortality benefit and reducing heart failure hospitalization 1, 4

Diuretics for Symptom Management

• Diuretics manage fluid retention and are essential when pulmonary congestion or peripheral edema is present 1

Non-Pharmacological Management

Patient Education and Self-Management

• Educate patients on heart failure pathophysiology, symptom recognition (dyspnea, edema, weight gain), and when to seek medical attention 2, 1
• Implement daily self-weighing to detect early fluid retention 2
• Emphasize strict adherence to both pharmacological and non-pharmacological prescriptions 2

Lifestyle Modifications

• Control sodium intake, particularly in severe heart failure 2, 1
• Avoid excessive fluid intake (typically limit to 1.5-2 liters daily in severe HF) and excessive alcohol consumption 2, 1
• Encourage daily physical and leisure activities in stable patients to prevent muscle deconditioning 2, 1
• Implement exercise training programs in stable NYHA II-III patients to improve exercise tolerance and quality of life 2, 1, 4
• Smoking cessation is mandatory; nicotine replacement therapies may be used 2

Travel Considerations

• Advise patients about potential problems with long flights, high altitudes, and hot humid climates, particularly regarding diuretic and vasodilator use 2

Device Therapy

Cardiac Resynchronization Therapy (CRT) and Implantable Cardioverter-Defibrillator (ICD)

• Specialist referral is warranted for consideration of CRT and ICD in patients with persistent symptoms despite optimal medical therapy 1

Monitoring and Follow-Up

Regular Laboratory Surveillance

• Monitor blood pressure, renal function (creatinine), and electrolytes (potassium) before treatment, 1-2 weeks after each dose increment, at 3 months, and then every 6 months 2
• More frequent monitoring is required when adding medications that affect renal function (aldosterone antagonists, ARBs) or in patients with pre-existing renal dysfunction 2
• During any hospitalization, reassess renal function and electrolytes 2

Common Pitfalls to Avoid

Medication Errors

• Never use potassium-sparing diuretics during ACE inhibitor initiation 2
• Avoid non-steroidal anti-inflammatory drugs (NSAIDs) as they worsen renal function and fluid retention 2
• Do not combine ACE inhibitors, ARBs, and MRAs due to excessive risk of hyperkalemia and renal dysfunction 4
• Avoid thiazide diuretics when GFR is less than 30 mL/min unless used synergistically with loop diuretics 2

Dosing Errors

• Do not accept starting doses as maintenance therapy; aggressive titration to target doses is essential for mortality benefit 2
• When temporary dose reduction is necessary, attempt restoration to target doses rather than accepting permanent dose reduction 2

Initiation Timing

• Ensure patients are relatively stable before initiating beta-blockers; avoid starting during acute decompensation or when intravenous inotropic support is required 2, 4
• If inotropic support is needed in a patient on beta-blockade, use phosphodiesterase inhibitors as their effects are not antagonized by beta-blockers 4