What medication classes decrease mortality in Heart Failure with Reduced Ejection Fraction (HFrEF)?

Medication Classes That Decrease Mortality in HFrEF

Four medication classes have proven mortality benefit in HFrEF and should be initiated simultaneously as soon as possible after diagnosis: ARNI/ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1, 2

The Four Pillars of Mortality-Reducing Therapy

1. Renin-Angiotensin System Inhibitors

ARNI (sacubitril/valsartan) is the preferred first-line agent over ACE inhibitors, providing 16-20% mortality reduction. 1, 2, 3

• ACE inhibitors reduce mortality by 17% when ARNI is not feasible, and are indicated for all patients with current or prior HFrEF symptoms unless contraindicated 1, 4
• ARBs are recommended for ACE inhibitor-intolerant patients (due to cough or angioedema), also reducing mortality by 17% 1
• ARNI provides incremental mortality benefit beyond ACE inhibitors, with a number needed to treat (NNT) of 36 over 27 months to prevent one death 1
• Critical contraindication: Never combine ACE inhibitor with ARNI—require 36-hour washout period when switching 2, 3

2. Beta-Blockers

Only three beta-blockers have proven mortality reduction: bisoprolol, carvedilol, and sustained-release metoprolol succinate—these reduce mortality by 30-34%, the largest effect of any single drug class. 1, 2, 5

• Beta-blockers provide an NNT of 28 over 12 months to prevent one death, standardizing to an NNT of 9 over 36 months 1
• These agents reduce sudden cardiac death by at least 20% 2
• Dose-dependent mortality benefit exists, with higher target doses showing superior outcomes compared to lower doses 1
• Common pitfall: Using non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate) provides no proven mortality benefit 2

3. Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone or eplerenone reduce mortality by 30% in patients with NYHA class II-IV symptoms and LVEF ≤35%. 1, 2

• MRAs provide an NNT of 9 over 24 months to prevent one death, standardizing to an NNT of 6 over 36 months—among the most potent mortality-reducing agents 1
• These agents reduce sudden cardiac death by at least 20% 2
• Mandatory monitoring requirements: Creatinine must be ≤2.5 mg/dL in men or ≤2.0 mg/dL in women (eGFR >30 mL/min/1.73 m²), and potassium must be <5.0 mEq/L at initiation 1
• Class III Harm recommendation: MRAs are potentially harmful when creatinine >2.5 mg/dL in men or >2.0 mg/dL in women, or potassium >5.0 mEq/L due to life-threatening hyperkalemia risk 1
• For NYHA class II patients specifically, require either prior cardiovascular hospitalization or elevated natriuretic peptides to justify MRA initiation 1

4. SGLT2 Inhibitors

SGLT2 inhibitors (empagliflozin or dapagliflozin) reduce mortality by 17% and cardiovascular death/HF hospitalization regardless of diabetes status. 1, 2, 6, 7

• SGLT2i provide an NNT of 43 over 18 months to prevent one death, standardizing to an NNT of 22 over 36 months 1
• Critical advantage: Minimal blood pressure effect makes them ideal first agents to initiate, even in patients with borderline low BP 2
• These agents reduce HF hospitalizations significantly and provide renal protection beyond cardiovascular benefits 1, 8

Combined Mortality Benefit

When all four drug classes are used together, the estimated reduction in all-cause mortality is 73% compared to no treatment. 1

• Network meta-analysis demonstrates that ARNI + beta-blocker + MRA reduces all-cause mortality by 62% (hazard ratio 0.38,95% CrI 0.20-0.65) 9
• ACE inhibitor + beta-blocker + MRA + ivabradine reduces all-cause mortality by 59% (hazard ratio 0.41,95% CrI 0.21-0.70) 9
• The incremental benefit of combining drug classes is additive and superior to any single agent 9

Additional Mortality-Reducing Therapies for Specific Populations

Hydralazine/Isosorbide Dinitrate

This combination reduces mortality by 43% specifically in self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 1, 2

• NNT of 25 over 10 months to prevent one death, standardizing to an NNT of 7 over 36 months 1
• May be inferior to ACE inhibitors for mortality in non-Black populations 2
• Starting dose: hydralazine 25 mg three times daily plus isosorbide dinitrate 20 mg three times daily 2

Device Therapies With Mortality Benefit

Cardiac resynchronization therapy (CRT) reduces mortality by 36% in patients with LVEF ≤35%, NYHA class II-III symptoms, QRS ≥150 msec with LBBB morphology in sinus rhythm. 1, 2

• CRT provides an NNT of 12 over 24 months to prevent one death, standardizing to an NNT of 8 over 36 months 1

Implantable cardioverter-defibrillator (ICD) reduces mortality by 23% in patients with symptomatic HF (NYHA class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy. 1, 2

• ICD provides an NNT of 14 over 60 months to prevent one death, standardizing to an NNT of 23 over 36 months 1
• Patients must have expected survival >1 year with good functional status 2

Critical Implementation Strategy

Initiate all four foundational medication classes simultaneously at low doses, then uptitrate one drug at a time every 1-2 weeks to target doses proven in clinical trials. 1, 2

• Start with SGLT2 inhibitor and MRA first (minimal BP effect), then add beta-blocker or low-dose ARNI 2
• Target doses from clinical trials: sacubitril/valsartan 97/103 mg twice daily, carvedilol 25 mg twice daily, bisoprolol 10 mg daily, metoprolol succinate 200 mg daily, spironolactone 25-50 mg daily 1, 3, 5
• 70-85% of patients in clinical trials achieved and maintained target doses with this strategy 1

Medications That Do NOT Reduce Mortality

Diuretics are essential for symptom control but provide no mortality benefit—they relieve congestion only. 1, 2

Ivabradine shows modest or negligible survival benefit in the broad HFrEF population, though it reduces HF hospitalizations. 2, 7

Digoxin has no proven mortality benefit and its importance has steadily decreased. 10

Common Pitfalls to Avoid

• Never delay initiation of all four medication classes—simultaneous initiation is now the standard of care 2
• Never accept suboptimal doses when higher target doses are tolerated—dose-dependent mortality benefit exists 1, 2
• Never stop medications for asymptomatic hypotension with adequate perfusion—low BP alone is not a contraindication 2
• Never combine ACE inhibitor + ARB + MRA (triple combination) due to hyperkalemia and renal dysfunction risk 2
• Never use diltiazem or verapamil in HFrEF—they increase risk of worsening heart failure and hospitalization 2