What medications have a proven mortality benefit in patients with heart failure with reduced ejection fraction (HFrEF)?

Medications with Proven Mortality Benefit in Heart Failure with Reduced Ejection Fraction

Four medication classes have proven mortality benefit in HFrEF and should be initiated in all eligible patients: ACE inhibitors (or ARNIs as replacement), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1

Core Foundational Therapies (Class I Recommendations)

First-Line Mortality-Reducing Medications

ACE Inhibitors (ACE-I)

• Reduce mortality and morbidity in all symptomatic HFrEF patients unless contraindicated 1
• Should be uptitrated to maximum tolerated dose for adequate RAAS inhibition 1
• Enalapril demonstrated 11% reduction in all-cause mortality and 30% reduction in HF hospitalization in the SOLVD trial 2
• Also indicated in asymptomatic LV systolic dysfunction to prevent HF development and death 1

Beta-Blockers

• Reduce mortality and morbidity when added to ACE-I therapy in stable, symptomatic HFrEF 1
• Should be initiated together with ACE-I as complementary therapy once HFrEF diagnosis is made 1
• Must be uptitrated to maximum tolerated dose 1
• Initiate at low dose in clinically stable patients, cautiously in hospitalized patients once stabilized 1

Mineralocorticoid Receptor Antagonists (MRAs)

• Indicated for patients remaining symptomatic despite ACE-I and beta-blocker therapy 1
• Spironolactone reduced risk of death by 30% in the RALES trial (p<0.001) 3
• Also reduced cardiac hospitalization by 30% 3
• Eplerenone indicated for stable patients with symptomatic HFrEF (≤40% EF) post-MI 4
• Critical exclusion criteria: baseline serum creatinine >2.5 mg/dL or potassium >5.0 mEq/L 1, 3

SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Recommended for all HFrEF patients to reduce HF hospitalization and death 1
• Demonstrated high certainty evidence for improved health-related quality of life (SMD 0.16,95% CI 0.08-0.23) 1
• Provide mortality benefit irrespective of diabetes status 5
• Also indicated for HFmrEF and HFpEF 1

Advanced Therapy for Persistent Symptoms

Sacubitril/Valsartan (ARNI)

• Recommended as replacement for ACE-I (not in addition to) in ambulatory HFrEF patients with persistent symptoms despite optimal therapy 1
• Superior to enalapril in reducing death and HF hospitalization in the PARADIGM-HF trial 1
• Reduces cardiovascular and all-cause death beyond ACE-I 1
• High certainty evidence for improved quality of life (SMD 0.09,95% CI 0.02-0.17) 1

Alternative Agents for ACE-I Intolerance

Angiotensin Receptor Blockers (ARBs)

• Recommended only for symptomatic HFrEF patients unable to tolerate ACE-I or ARNI 1
• Have not been consistently proven to reduce mortality 1
• Use restricted to ACE-I intolerant patients or those unable to tolerate MRA while on ACE-I 1
• High certainty evidence for improved quality of life (SMD 0.09,95% CI 0.02-0.17) 1

Quantified Survival Benefit

Quadruple therapy (ARNi/beta-blocker/MRA/SGLT2i) provides approximately 5.3 additional life-years for a 70-year-old patient versus no treatment 6. For a 55-year-old patient, transitioning from traditional dual therapy (ACE-I + beta-blocker) to quadruple therapy extends life expectancy by 6 years 1. Compared to no treatment, quadruple therapy reduces risk of death by 73% over 2 years 1.

Additional Considerations

Ivabradine

• Should be considered when heart rate remains elevated despite optimal therapy 1
• High certainty evidence for improved quality of life (SMD 0.14,95% CI 0.04-0.23) 1

Hydralazine-Nitrate

• High certainty evidence for improved quality of life (SMD 0.24,95% CI 0.04-0.44) 1

Diuretics

• Recommended for symptom relief and exercise capacity in patients with congestion 1
• Do not have proven mortality benefit but essential for symptom management 1
• Loop diuretics preferred over thiazides 7

Critical Implementation Points

• All four foundational therapies (ACE-I or ARNI, beta-blocker, MRA, SGLT2i) should be initiated rapidly and simultaneously or in rapid sequence, not sequentially over months 1, 8
• Target maximum tolerated doses for all agents 1
• Major gaps persist in real-world utilization despite strong evidence 1
• Avoid: Diltiazem and verapamil increase risk of HF worsening and hospitalization 1
• Avoid: Triple RAAS blockade (ACE-I + ARB + MRA) due to renal dysfunction and hyperkalemia risk 1