What are the benefits of each of the 4 goal-directed therapy medications, including Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), Beta-Blockers, and Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, in heart failure?

Benefits of the Four Goal-Directed Therapy Medications in Heart Failure

ACE Inhibitors and ARBs

ACE inhibitors or ARBs reduce all-cause mortality by 17% and are foundational first-line therapies for heart failure with reduced ejection fraction (HFrEF). 1

• Mortality reduction: ACE inhibitors/ARBs decrease all-cause mortality with a number needed to treat (NNT) of 22 over 42 months, which standardizes to an NNT of 26 over 36 months 1
• Hospitalization benefits: These agents reduce hospital admissions by 99 per 1000 patient-years of treatment 1
• Symptom improvement: ACE inhibitors improve NYHA functional class and quality of life in patients with symptomatic heart failure 1
• Disease progression: ACE inhibitors delay or prevent the development of symptomatic heart failure in patients with asymptomatic left ventricular systolic dysfunction 1
• Post-MI protection: In patients with systolic dysfunction after acute myocardial infarction, ACE inhibitors significantly increase survival 1

ARBs serve as suitable substitutes when ACE inhibitors cannot be tolerated due to side effects like cough, providing similar mortality and morbidity benefits 2, 3

Beta-Blockers

Beta-blockers provide the most robust mortality benefit among heart failure medications, reducing all-cause mortality by 34% with an NNT of only 9 over 36 months. 1

• Mortality reduction: Beta-blockers achieve a consistent 30% reduction in mortality across multiple trials 1
• Hospitalization reduction: These agents reduce hospitalizations by 40% in patients with NYHA class II and III heart failure, translating to 65 fewer hospital admissions per 1000 patient-years 1
• Functional improvement: Beta-blockers improve NYHA functional class and quality of life in heart failure patients 1
• Broad applicability: Benefits extend to patients with NYHA class II through IV heart failure, with over 10,000 patients studied in randomized controlled trials 1
• Specific agents: Bisoprolol, carvedilol, and metoprolol succinate are the evidence-based beta-blockers with proven efficacy in HFrEF 1

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs reduce all-cause mortality by 30% with an NNT of only 6 over 36 months, representing one of the most potent mortality benefits in heart failure therapy. 1

• Mortality reduction: MRAs (spironolactone or eplerenone) reduce the risk of cardiovascular death by 30%, with particularly strong effects on sudden cardiac death 1
• Hospitalization benefits: These agents reduce hospital admissions by 138 per 1000 patient-years, the highest reduction among all heart failure medications 1
• Post-MI benefit: Eplerenone improves survival in stable patients with symptomatic HFrEF after acute myocardial infarction 4
• Blood pressure control: Spironolactone is particularly beneficial in HFmrEF patients with poorly controlled hypertension 1
• Dosing: Spironolactone typically starts at 12.5-25 mg daily with a target of 25-50 mg daily; eplerenone starts at 25 mg daily with a target of 50 mg daily 5

SGLT2 Inhibitors

SGLT2 inhibitors reduce all-cause mortality by 17% and hospitalization for heart failure by 27-39%, with benefits occurring within weeks of initiation regardless of diabetes status. 1, 6

• Mortality and hospitalization: SGLT2 inhibitors reduce the composite endpoint of cardiovascular death or heart failure hospitalization by 21-26%, driven primarily by a 29% reduction in heart failure hospitalizations 1, 6
• Rapid benefit: Clinical benefits appear within weeks of initiation and are maintained long-term 6
• Diabetes-independent: Benefits are consistent in patients with and without diabetes mellitus 1, 7
• Renal protection: SGLT2 inhibitors decrease the slope of eGFR decline and reduce the risk of chronic kidney disease progression 1, 6
• Quality of life: These agents produce modest but significant improvements in quality of life at 52 weeks 1
• Broad applicability: Effective across the ejection fraction spectrum, including HFrEF and HFpEF (LVEF >40%) 1, 6
• No titration required: Unlike other heart failure medications, SGLT2 inhibitors do not require dose adjustment or uptitration and have minimal impact on blood pressure, heart rate, or potassium levels 6
• Specific agents: Dapagliflozin 10 mg daily and empagliflozin 10 mg daily are the recommended SGLT2 inhibitors with proven mortality and hospitalization benefits 5

Comprehensive Quadruple Therapy Benefits

When used together as comprehensive quadruple therapy (ARNI/ACE inhibitor + beta-blocker + MRA + SGLT2 inhibitor), these medications reduce the risk of death by 73% over 2 years compared to no treatment. 1

• Life expectancy gains: Transitioning a 55-year-old patient from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy extends life expectancy by approximately 6 years 1
• Event-free survival: Comprehensive therapy affords 2.7 additional years (for an 80-year-old) to 8.3 additional years (for a 55-year-old) free from cardiovascular death or first heart failure hospitalization 8
• Aggregate effect: The hazard ratio for comprehensive therapy versus conventional therapy on cardiovascular death or heart failure hospitalization is 0.38 (95% CI 0.30-0.47), representing a 62% risk reduction 8