What are the target doses of Guideline-Directed Medical Therapy (GDMT) for heart failure?

Target Doses of Guideline-Directed Medical Therapy (GDMT) for Heart Failure

The target doses of GDMT for heart failure with reduced ejection fraction (HFrEF) are well-established in clinical guidelines, and patients should be titrated to these doses whenever possible to reduce morbidity and mortality. 1

ACE Inhibitors Target Doses

• Captopril: 50 mg three times daily (total daily dose: 150 mg) 1
• Enalapril: 10 mg twice daily (total daily dose: 20 mg) 1, 2
• Lisinopril: 20 mg once daily 1
• Ramipril: 10 mg once 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 (total daily dose: 40 mg) 1

ARBs Target Doses

• Candesartan: 32 mg once daily 1
• Losartan: 100 mg once daily 1
• Valsartan: 160 mg twice daily (total daily dose: 320 mg) 1, 3
• Irbesartan: 300 mg once daily 1
• Telmisartan: 80 mg once daily 1
• Olmesartan: 40 mg once daily 1
• Azilsartan: 80 mg once daily 1, 4

ARNI Target Dose

• Sacubitril/valsartan: 97/103 mg twice daily (total daily dose: 194/206 mg) 1

Evidence-Based Beta-Blockers Target Doses

• Bisoprolol: 10 mg once daily 1
• Carvedilol: 25 mg twice daily (total daily dose: 50 mg) 1
• Carvedilol extended release: 80 mg once daily 1
• Metoprolol succinate sustained release: 200 mg once daily 1

Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone: 25-50 mg once daily 1, 5
• Eplerenone: 50 mg once daily 1

SGLT2 Inhibitors

• Dapagliflozin: 10 mg once daily 1
• Empagliflozin: 10 mg once daily 1

Importance of Dose Titration

• Studies have supported a dose-response relationship between GDMT and improved outcomes, suggesting that treating at less than target dose may result in worse clinical outcomes 1
• Despite guideline recommendations, the percentage of patients achieving target doses remains low in clinical practice 1, 6
• In clinical trials, higher doses have provided greater benefits than lower doses, with little evidence that subtarget doses yield comparable survival benefits 1

Titration Strategy

• GDMT should be initiated at low doses and titrated upward to target doses 1
• Therapies should be adjusted no more frequently than every 2 weeks to target doses or maximally tolerated doses 1, 3
• Beta-blockers should be initiated at very low doses, followed by gradual incremental increases if lower doses have been well tolerated 1

Minimum Effective Dosing

• At minimum, patients should receive at least 50% of the target dose of each medication class for adequate treatment effect 1
• For example, 50% of target doses would be:
  • ACE inhibitors: varies by medication (e.g., enalapril 10 mg daily) 1
  • ARBs: varies by medication (e.g., valsartan 160 mg daily) 1
  • Beta-blockers: varies by medication (e.g., carvedilol 25 mg daily) 1
  • ARNI: sacubitril/valsartan 49/51 mg twice daily 1

Common Barriers to Target Dose Achievement

• Hypotension, renal dysfunction, and hyperkalemia are the most common barriers to GDMT initiation and uptitration 7, 8
• In elderly patients (≥80 years), target doses are achieved in only a small percentage of patients (19% for beta-blockers, 7% for RAS inhibitors) 7
• Patient-level factors such as acute kidney injury and non-compliance often limit dose titration 8

Clinical Approach to Optimization

• Make every effort to achieve target doses shown to be effective in major clinical trials 1
• If dose reduction is necessary due to side effects, attempt to restore target doses when possible 1, 3
• In clinical trials, approximately 40% of patients who required temporary dose reduction were subsequently restored to target doses 1
• Recent guidelines emphasize starting all four key life-saving therapies (ACEi/ARB/ARNI, beta-blockers, MRAs, SGLT2i) as quickly as possible, with titration to target doses as a secondary consideration 9

Important Considerations

• Despite the emphasis on target doses, many patients in clinical trials achieved benefits with average doses that were less than target 9
• Adverse events are common in heart failure patients but are often not attributable to GDMT; rates of adverse events are similar between active medication and placebo in clinical trials 1
• The approach to treating heart failure differs from treating cancer, with heart failure treatment often prioritizing avoidance of adverse effects over aggressive dosing, despite heart failure being more lethal than most forms of cancer 1