What are the target doses for medications in heart failure management, including Angiotensin-Converting Enzyme (ACE) inhibitors, beta-blockers, Angiotensin Receptor-Neprilysin Inhibitors (ARNI), mineralocorticoid receptor antagonists, and Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

Target Doses for Heart Failure Medications

All patients with HFrEF should be titrated to the specific target doses established in landmark clinical trials, as these doses have been proven to reduce mortality and morbidity, with uptitration occurring every 2 weeks as tolerated. 1

ACE Inhibitors - Target Doses

The following target doses are derived from mortality-reducing trials 1:

• Enalapril: 10 mg twice daily (20 mg total daily) 1
• Lisinopril: 20 mg once daily 1
• Ramipril: 10 mg once daily 1
• Captopril: 50 mg three times daily (150 mg total daily) 1
• Perindopril: 8 mg once daily 1
• Trandolapril: 4 mg once daily 1
• Benazepril: 40 mg once daily 1
• Fosinopril: 40 mg once daily 1
• Quinapril: 20 mg twice daily (40 mg total daily) 1

Angiotensin Receptor Blockers (ARBs) - Target Doses

ARBs are recommended when ACE inhibitors are not tolerated 1:

• Candesartan: 32 mg once daily 1
• Valsartan: 160 mg twice daily (320 mg total daily) 1
• Losartan: 100 mg once daily (guidelines recommend 150 mg, but FDA maximum is 100 mg) 1
• Irbesartan: 300 mg once daily 1
• Telmisartan: 80 mg once daily 1
• Olmesartan: 40 mg once daily 1
• Azilsartan: 80 mg once daily 1

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) - Target Dose

Sacubitril/valsartan is preferred over ACE inhibitors or ARBs in NYHA class II-III patients to further reduce morbidity and mortality 2:

• Sacubitril/valsartan: 97/103 mg twice daily (194/206 mg total daily) 1
• Starting dose: 49/51 mg twice daily (or 24/26 mg twice daily in certain patients) 1
• The 49/51 mg twice daily dose is considered 50% of target 1

Beta-Blockers - Target Doses

Only three beta-blockers have proven mortality reduction in HFrEF and should be used 1, 2:

• Carvedilol: 25 mg twice daily (50 mg total daily; 50 mg twice daily for patients >85 kg) 1
• Carvedilol extended release: 80 mg once daily 1
• Metoprolol succinate (extended release): 200 mg once daily 1
• Bisoprolol: 10 mg once daily 1

Beta-blockers provide the highest relative mortality reduction (34%) among the four foundational medication classes 2.

Mineralocorticoid Receptor Antagonists (MRAs) - Target Doses

MRAs provide substantial mortality benefit with a number needed to treat of 6 over 36 months 2:

• Spironolactone: 25 mg once daily (can increase to 25 mg twice daily or 50 mg once daily) 1
• Eplerenone: 50 mg once daily 1

Starting doses are 12.5-25 mg daily for spironolactone and 25 mg daily for eplerenone 1.

SGLT2 Inhibitors - Doses

SGLT2 inhibitors are now recommended as foundational therapy in all patients with HFrEF, initiated simultaneously with other GDMT 2, 3:

• Dapagliflozin: 10 mg once daily 3
• Empagliflozin: 10 mg once daily 3

These medications have fixed dosing without titration requirements 3.

Critical Implementation Principles

All four medication classes (ACEi/ARB/ARNI, beta-blockers, MRAs, and SGLT2 inhibitors) should be initiated simultaneously at low doses as soon as HFrEF is diagnosed, regardless of symptom severity 2. This represents a paradigm shift from sequential therapy.

Uptitration should occur at 2-week intervals to target doses, not stopping at doses where symptoms improve 1, 2. The dose-response relationship demonstrates that target doses provide superior outcomes compared to lower doses 1.

At minimum, patients should achieve 50% of target doses 1. Studies show that doses below 50% of target may result in worse clinical outcomes 1.

Common Pitfalls to Avoid

Do not delay initiation of all four medication classes due to polypharmacy concerns 2. The mortality benefit of simultaneous initiation outweighs theoretical risks.

Do not fail to uptitrate to target doses used in clinical trials 1, 2. In clinical practice, less than 25% of patients reach target ARNI doses, and only 25-32% reach target beta-blocker doses 1, 4. However, studies demonstrate that 24% of patients initially unable to tolerate higher doses can successfully uptitrate with careful monitoring 4.

Do not permanently reduce doses without attempting re-titration 1. In PARADIGM-HF, 40% of patients requiring temporary dose reduction were successfully restored to target doses 1.

Do not use non-evidence-based beta-blockers 1, 2. Only bisoprolol, carvedilol, and metoprolol succinate have proven mortality reduction.

Monitor renal function and electrolytes before initiation and periodically during uptitration 2. The most dramatic blood pressure decreases occur with starting doses, not subsequent increments 1.

Target doses for hypertension are typically lower than HFrEF target doses 1. For example, candesartan for hypertension is 4-8 mg daily versus 32 mg daily for HFrEF; valsartan is 40-80 mg daily versus 320 mg daily 1.