How do medications for heart failure, such as Angiotensin-Converting Enzyme (ACE) inhibitors, beta-blockers, Angiotensin II Receptor Blockers (ARBs), and Angiotensin Receptor-Neprilysin Inhibitors (ARNIs), work to reduce morbidity and mortality?

Mechanisms of Heart Failure Medications

Heart failure medications work by blocking harmful neurohormonal pathways that drive disease progression, with ACE inhibitors, beta-blockers, ARNIs, and mineralocorticoid receptor antagonists each reducing mortality by at least 20% through distinct but complementary mechanisms. 1

Core Medication Classes and Their Mechanisms

ACE Inhibitors

ACE inhibitors block the conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion 1. They also inhibit kininase, which increases bradykinin levels—this contributes to beneficial vasodilation but causes cough in up to 20% of patients 1.

• Mortality benefit: 5-16% reduction in death risk, though they do not reduce sudden cardiac death 1
• Hemodynamic effects: Reduce afterload and preload, decrease cardiac remodeling 1
• Clinical outcomes: Proven to reduce morbidity and mortality across mild, moderate, and severe heart failure (NYHA Class II-IV) 1

Important caveat: ACE inhibitors provide modest survival benefit compared to other neurohormonal antagonists, and intensifying the dose does not enhance survival benefit 1.

Beta-Blockers

Beta-blockers (specifically carvedilol, metoprolol succinate, and bisoprolol) block adrenergic receptors, counteracting the harmful effects of chronic sympathetic nervous system activation 1.

• Mortality benefit: At least 20% reduction in death risk 1
• Sudden death reduction: Unlike ACE inhibitors, beta-blockers significantly reduce sudden cardiac death 1
• Mechanism: Reduce heart rate, decrease myocardial oxygen demand, prevent arrhythmias, and reverse cardiac remodeling 1
• Initiation: Must be started at low doses in clinically stable patients already on ACE inhibitors, then uptitrated to target doses proven in trials 1

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

ARNIs combine an ARB (valsartan) with a neprilysin inhibitor (sacubitril), providing dual mechanism action 1.

• Neprilysin inhibition: Prevents breakdown of natriuretic peptides (BNP, ANP), bradykinin, and adrenomedullin—all beneficial vasodilatory substances 1
• ARB component: Blocks angiotensin II at the receptor level 1
• Mortality benefit: 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril—the most robust benefit among all drug classes 1, 2
• Sudden death reduction: Yes, similar to beta-blockers and mineralocorticoid antagonists 1

Critical evidence: The PARADIGM-HF trial demonstrated sacubitril/valsartan reduced the composite endpoint of CV death or HF hospitalization (HR 0.80, p<0.0001) and improved all-cause mortality (HR 0.84, p=0.0009) compared to enalapril in patients with NYHA Class II-IV heart failure 2.

Angiotensin Receptor Blockers (ARBs)

ARBs block angiotensin II at the AT1 receptor level, providing more complete blockade than ACE inhibitors since alternative pathways (non-ACE) also produce angiotensin II 1.

• Mortality benefit: Similar to ACE inhibitors, reducing morbidity and mortality 1
• Side effect advantage: Significantly lower incidence of cough and angioedema compared to ACE inhibitors because they do not affect bradykinin 1, 3
• Clinical role: Recommended only for patients intolerant to ACE inhibitors due to cough or angioedema 1, 4

Important distinction: ARBs are NOT equivalent to ACE inhibitors when combined with beta-blockers—the evidence base for ARB + beta-blocker combination is weak except for candesartan 5. ACE inhibitors remain preferred first-line therapy 4, 3.

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs (spironolactone, eplerenone) block aldosterone receptors, preventing sodium retention, potassium loss, and cardiac fibrosis 1.

• Mortality benefit: At least 20% reduction in death risk 1
• Sudden death reduction: Yes, proven benefit 1
• Indication: NYHA Class III-IV heart failure on background ACE inhibitor and diuretic therapy 1
• Monitoring: Check potassium and creatinine 5-7 days after initiation; avoid if K+ >5.0 mEq/L or eGFR <30 mL/min 1

Treatment Hierarchy and Algorithm

The evidence-based treatment sequence for heart failure with reduced ejection fraction:

1. First-line combination: ARNI (sacubitril/valsartan) + beta-blocker + MRA for NYHA Class II-III patients who tolerate ACE inhibitors/ARBs 1, 4

2. Alternative if ARNI not appropriate: ACE inhibitor + beta-blocker + MRA 1

3. If ACE inhibitor intolerant: ARB + beta-blocker + MRA (only for cough or angioedema) 1, 4

Critical implementation principle: All medications should be initiated at low doses and uptitrated to target doses proven in clinical trials using a "forced-titration" strategy 1. Asymptomatic changes in vital signs or labs should not prevent uptitration—only persistent, clinically meaningful adverse events warrant dose reduction 1.

Common Pitfalls to Avoid

• Never combine ACE inhibitor + ARB: Increases adverse effects without mortality benefit 3
• Do not delay beta-blockers or MRAs: These reduce sudden death and cannot be reasonably delayed even in stable patients 1
• Avoid NSAIDs: They antagonize the benefits of ACE inhibitors and ARBs 1
• Monitor renal function closely: Check creatinine, potassium, and blood pressure 1-2 weeks after initiation, after each dose increase, at 3 months, then every 6 months 1, 4
• ARNI timing: Must wait 36 hours after stopping ACE inhibitor before starting ARNI to avoid angioedema risk 3
• Pregnancy: ACE inhibitors and ARBs are contraindicated 1

Drugs with Limited Mortality Benefit

Digoxin and ivabradine primarily reduce hospitalizations but have modest or negligible survival benefit in the broad HFrEF population 1. They receive Class II recommendations and are considered adjunctive rather than essential therapy 1.