What medications are included in Guideline-Directed Medical Therapy (GDMT) for heart failure?

Guideline-Directed Medical Therapy (GDMT) for Heart Failure

GDMT consists of four foundational medication classes for heart failure with reduced ejection fraction (HFrEF): ACE inhibitors/ARBs/ARNI (angiotensin receptor-neprilysin inhibitor), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors (sodium-glucose cotransporter 2 inhibitors). 1, 2

Core GDMT Medications for HFrEF

1. Renin-Angiotensin System (RAS) Inhibitors (Class I Recommendation)

ACE Inhibitors:

• Enalapril: 2.5 mg twice daily initially, target 10-20 mg twice daily 1
• Lisinopril: 2.5-5 mg daily initially, target 20-40 mg daily 1
• Captopril: 6.25 mg three times daily initially, target 50 mg three times daily 1
• Ramipril: 1.25-2.5 mg daily initially, target 10 mg daily 1

Angiotensin Receptor Blockers (ARBs):

• Valsartan: 20-40 mg twice daily initially, target 160 mg twice daily 1
• Candesartan: 4-8 mg daily initially, target 32 mg daily 1
• Losartan: 25-50 mg daily initially, target 50-150 mg daily 1

ARNI (Preferred over ACE inhibitors/ARBs):

• Sacubitril/valsartan: 49/51 mg twice daily initially, target 97/103 mg twice daily 1, 3
• Must discontinue ACE inhibitors 36 hours before initiating ARNI to avoid angioedema 3
• Provides at least 20% mortality reduction, superior to ACE inhibitors/ARBs 2

2. Evidence-Based Beta-Blockers (Class I Recommendation)

Only three beta-blockers have proven mortality benefit:

• Carvedilol: 3.125 mg twice daily initially, target 50 mg twice daily 1
• Metoprolol succinate (extended-release): 12.5-25 mg daily initially, target 200 mg daily 1
• Bisoprolol: 1.25 mg daily initially, target 10 mg daily 1

These provide at least 20% mortality reduction in HFrEF 2. Selective β₁ receptor blockers may be preferred in patients with low blood pressure due to lesser BP-lowering effects 1.

3. Mineralocorticoid Receptor Antagonists (Class I Recommendation)

• Spironolactone: 12.5-25 mg daily initially, target 25 mg daily or twice daily 1
• Eplerenone: 25 mg daily initially, target 50 mg daily 1
• Provide at least 20% mortality reduction 2
• Require monitoring of potassium (contraindicated if K+ >5.0 mEq/L) and creatinine clearance >30 mL/min 1

4. SGLT2 Inhibitors (Class I Recommendation)

• Dapagliflozin or empagliflozin 2
• Newest class added to HFrEF therapy with significant mortality benefits 2
• Do not lower blood pressure, making them ideal first-line agents in hypotensive patients 1
• Also recommended for HFpEF (Class 2a) 2

Additional GDMT Medications

Hydralazine-Isosorbide Dinitrate (Class I for Black Patients)

• Fixed-dose combination: 20 mg isosorbide dinitrate/37.5 mg hydralazine three times daily initially, target 40 mg/75 mg three times daily 1
• Stronger recommendation in ACC/AHA/HFSA guidelines (Class I) versus ESC (Class IIa) 1
• Particularly beneficial in Black patients with NYHA class III-IV heart failure 1

Ivabradine (Class IIa Recommendation)

• 5 mg twice daily initially, target 7.5 mg twice daily 1
• For patients in sinus rhythm with heart rate ≥70 bpm on maximally tolerated beta-blocker doses 1
• Alternative when beta-blockers are not hemodynamically tolerated 1

Combined Therapy Impact

Quadruple therapy (ARNI + beta-blocker + MRA + SGLT2i) reduces mortality risk by approximately 73% over 2 years compared to no treatment. 2 Transitioning from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy can extend life expectancy by approximately 6 years 2.

Initiation Strategy in Low Blood Pressure Patients

For patients with systolic BP <90 mmHg but adequate perfusion:

1. Start with medications that don't lower BP: SGLT2 inhibitors and MRAs first 1
2. Add heart rate control if HR >70 bpm: Low-dose beta-blocker (preferably selective β₁ blocker) 1
3. Add RAS inhibition: Very low-dose sacubitril/valsartan (25 mg twice daily) or low-dose ACE inhibitor 1
4. Titrate slowly: Small increments every 1-2 weeks, one drug at a time 1
5. Consider ivabradine: If beta-blockers not tolerated hemodynamically 1

GDMT for Heart Failure with Preserved Ejection Fraction (HFpEF)

Primary medications differ significantly from HFrEF:

• SGLT2 inhibitors: Strongest recommendation (Class 2a) based on DELIVER and EMPEROR-PRESERVED trials showing reduction in HF hospitalizations and cardiovascular death 2
• MRAs: Weaker recommendation (Class 2b) for reducing HF hospitalizations 2
• Diuretics: Class I for symptom relief in volume-overloaded patients 1
• Blood pressure control: Class I recommendation as cornerstone of management 1, 2
• Atrial fibrillation management: Class 2a for symptom improvement 2

ARBs (candesartan), ACE inhibitors, and ARNI have only Class IIb recommendations for HFpEF, primarily for reducing hospitalizations rather than mortality 1, 2.

Critical Contraindications and Monitoring

ACE inhibitors/ARBs/ARNI:

• Contraindicated with history of angioedema 3
• Cannot combine ACE inhibitor with ARNI 3
• Monitor creatinine and potassium 1

Beta-blockers:

• Avoid combining verapamil or diltiazem with beta-blockers in atrial fibrillation 1

MRAs:

• Contraindicated if creatinine clearance <30 mL/min or K+ >5.0 mEq/L 1
• Monitor for hyperkalemia (5.7% higher rate with MRAs) and gynecomastia in males (avoidable with eplerenone) 1

Common Pitfalls

Adverse events are common in HF patients (74.9-84.5% in trials) but occur at similar rates in placebo and intervention arms, suggesting symptoms are often due to heart failure itself rather than GDMT. 1 Providers should not automatically attribute symptoms to medications and should consider re-trialing medications if previously stopped 1.

Only 1% of eligible patients achieve target doses of all GDMT medications simultaneously in real-world practice. 1 However, even achieving <50% of target doses provides mortality benefit, though optimal dosing provides greatest benefit 1.

Patients with improved ejection fraction (HFimpEF) from <40% to >40% must continue their HFrEF GDMT regimen, as discontinuation leads to clinical deterioration. 2