What are the dosing guidelines for the 4 pillars of heart failure management, including Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), beta-blockers, and diuretics?

Dosing Guidelines for the Four Pillars of Heart Failure Management

The four pillars of heart failure management (ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors) should be initiated at low doses and titrated to target doses that have demonstrated mortality benefit in clinical trials, with careful monitoring of blood pressure, heart rate, renal function, and electrolytes throughout the process.

ACE Inhibitors/ARBs/ARNi

Initial and Target Doses

Medication	Initial Dose	Target Dose	Mean Dose in Clinical Trials
ACE Inhibitors
Captopril	6.25 mg three times daily	50 mg three times daily	122.7 mg/day
Enalapril	2.5 mg twice daily	10-20 mg twice daily	16.6 mg/day
Lisinopril	2.5-5 mg once daily	20-40 mg once daily	32.5-35.0 mg/day
Ramipril	1.25-2.5 mg once daily	10 mg once daily	N/A
ARBs
Candesartan	4-8 mg once daily	32 mg once daily	24 mg/day
Losartan	25-50 mg once daily	50-150 mg once daily	129 mg/day
Valsartan	20-40 mg twice daily	160 mg twice daily	254 mg/day
ARNi
Sacubitril-valsartan	49/51 mg twice daily	97/103 mg twice daily	182/193 mg/day

Initiation Protocol

1. Review need for and dose of diuretics and vasodilators
2. Avoid excessive diuresis before treatment; reduce or withhold diuretics for 24 hours if possible
3. Start with a low dose and build up to recommended target doses
4. Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment
5. Avoid potassium-sparing diuretics during initiation
6. Avoid NSAIDs

Beta-Blockers

Initial and Target Doses

Medication	Initial Dose	Target Dose	Mean Dose in Clinical Trials
Bisoprolol	1.25 mg once daily	10 mg once daily	8.6 mg/day
Carvedilol	3.125 mg twice daily	25-50 mg twice daily	37 mg/day
Metoprolol succinate	12.5-25 mg once daily	200 mg once daily	159 mg/day

Initiation Protocol

1. Start with a low dose in stable patients (NYHA class II-IV)
2. Double dose at not less than 2-week intervals
3. Aim for target dose or highest tolerated dose
4. Monitor heart rate, blood pressure, clinical status, and body weight
5. Check blood chemistry 12 weeks after initiation and 12 weeks after final dose titration

Cautions

• Avoid in severe (NYHA class IV) CHF without specialist advice
• Avoid in recent (4 weeks) exacerbation of CHF
• Avoid in heart block or heart rate < 60/min
• Avoid in persisting signs of congestion

Mineralocorticoid Receptor Antagonists

Initial and Target Doses

Medication	Initial Dose	Target Dose	Mean Dose in Clinical Trials
Spironolactone	12.5-25 mg once daily	25-50 mg once daily	26 mg/day
Eplerenone	25 mg once daily	50 mg once daily	42.6 mg/day

Initiation Protocol

1. Start with low dose
2. Check serum potassium and creatinine after 5-7 days
3. Titrate accordingly
4. Recheck every 5-7 days until potassium values are stable

SGLT2 Inhibitors

Initial and Target Doses

Medication	Initial Dose	Target Dose	Mean Dose in Clinical Trials
Dapagliflozin	10 mg once daily	10 mg once daily	9.8 mg/day
Empagliflozin	10 mg once daily	10 mg once daily	N/A

Diuretics

Initial and Target Doses

• Loop diuretics or thiazides as needed for fluid overload
• If insufficient response:
  • Increase dose of diuretic
  • Combine loop diuretics and thiazides
  • With persistent fluid retention: administer loop diuretics twice daily
  • In severe chronic heart failure: add metolazone with frequent measurement of creatinine and electrolytes

Sequencing Strategy for Initiation

Recent evidence suggests a rapid sequencing approach for initiating all four foundational therapies within 2-4 weeks 1:

1. Step 1: Simultaneous initiation of a beta-blocker and SGLT2 inhibitor
2. Step 2 (1-2 weeks later): Initiation of sacubitril/valsartan (or ACE inhibitor/ARB)
3. Step 3 (1-2 weeks later): Addition of mineralocorticoid receptor antagonist

Monitoring and Problem Solving

For Worsening Symptoms

• If increasing congestion: double dose of diuretic and/or halve dose of beta-blocker
• If marked fatigue/bradycardia: halve dose of beta-blocker
• If serious deterioration: halve dose of beta-blocker or seek specialist advice

For Low Heart Rate

• If < 50 beats/min with worsening symptoms: halve dose of beta-blocker
• Review need for other heart rate slowing drugs (digoxin, amiodarone, diltiazem)
• Arrange ECG to exclude heart block
• Seek specialist advice

For Hypotension

• For asymptomatic low blood pressure: usually no change needed
• For symptomatic hypotension:
  • Reconsider need for nitrates, calcium channel blockers, and other vasodilators
  • If no signs of congestion, consider reducing diuretic dose

Important Considerations

• Never abruptly discontinue beta-blockers unless absolutely necessary due to risk of rebound effects 2, 3
• Remember that some beta-blocker is better than no beta-blocker 2
• Patients should be encouraged to weigh themselves daily and increase diuretic dose if weight increases by 1.5-2.0 kg over 2 days 2, 3
• The benefits of beta-blockers cannot be assumed to be a class effect in heart failure; use only the three proven agents (bisoprolol, carvedilol, metoprolol succinate) 2
• Target doses were the ones that established efficacy and safety in clinical trials, so aim for these doses whenever possible 2

By following these dosing guidelines and monitoring protocols, clinicians can optimize the benefits of the four pillars of heart failure management while minimizing adverse effects, ultimately improving mortality, morbidity, and quality of life for patients with heart failure.