What has the best mortality benefit in Guideline-Directed Medical Therapy (GDMT) for patients with heart failure or coronary artery disease?

Mortality Benefit in Guideline-Directed Medical Therapy

Among individual GDMT components for heart failure with reduced ejection fraction, beta-blockers, ARNI (sacubitril/valsartan), and mineralocorticoid receptor antagonists each provide approximately 20% reduction in mortality risk, while ACE inhibitors/ARBs provide 5-16% reduction—making beta-blockers, ARNI, and MRAs the strongest individual mortality-reducing therapies. 1, 2

Individual Medication Class Mortality Benefits

Highest Mortality Reduction (≥20%)

• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) provide at least 20% reduction in mortality risk in HFrEF patients 1, 2

• ARNI (sacubitril/valsartan) provides at least 20% reduction in mortality risk, superior to ACE inhibitors/ARBs 1, 2

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) provide at least 20% reduction in mortality risk 1, 2

Moderate Mortality Reduction

• ACE inhibitors or ARBs reduce mortality by 5-16% in HFrEF patients 1, 2

• SGLT2 inhibitors (dapagliflozin or empagliflozin) have significant mortality benefits, though the exact percentage reduction is not specified in the guidelines 1, 2

The Synergistic Effect: Quadruple Therapy Superiority

The most critical finding is that combined quadruple therapy (ARNI/ACEi/ARB + beta-blocker + MRA + SGLT2 inhibitor) reduces mortality risk by approximately 73% over 2 years compared to no treatment—far exceeding any single agent. 1, 2

• Transitioning from traditional dual therapy (ACE inhibitor and beta-blocker) to quadruple therapy extends life expectancy by approximately 6 years 1, 2

• Each additional GDMT medication provides incremental mortality benefit, with the combined effect being multiplicative rather than simply additive 3

• The use of all four therapies in GDMT reduces mortality in HFrEF patients by 25% over 2 years, with each additional therapy providing incremental benefit 3

Clinical Context and Implementation

Why Individual Comparisons Are Misleading

The question of "which single medication has the best mortality benefit" misses the fundamental principle of modern HF management: these medications work through distinct and independent mechanisms, and withholding any component deprives patients of substantial survival benefit. 3

• Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications 1, 2

• In real-world practice, only 2.2% of HFrEF patients tolerate target doses of all three traditional GDMT medications (before SGLT2i era) 3

Evidence from Clinical Trials

• In the STICH trial of patients with CAD and HFrEF, GDMT adherence (defined as antiplatelet drug, statin, beta-blocker, and ACE inhibitor/ARB) was independently associated with 35% reduction in mortality (HR 0.65,95% CI 0.56-0.76) 4

• In the Danish Heart Failure Registry analysis of 46,816 patients, initiation of 3-4 GDMTs at 4 weeks was associated with 35% lower 1-year all-cause mortality (HR 0.65,95% CI 0.55-0.78) and 33% lower 3-year mortality (HR 0.67,95% CI 0.59-0.76) compared to no GDMT 5

• In severe HFrEF patients with advanced HF markers, treatment with beta-blockers was associated with 37% lower risk of death or HF hospitalization (adjusted HR 0.63,95% CI 0.48-0.84), and ACEi/ARB/ARNI with 26% lower risk (HR 0.74,95% CI 0.58-0.95) 6

Critical Implementation Strategy

All four foundational medications should be started simultaneously at low initial doses rather than sequential initiation, as this approach maximizes early mortality benefit without increasing serious adverse events. 1, 2

• The STRONG-HF trial demonstrated that simultaneous and rapid sequence initiation came with no significant increase in serious adverse events 3

• Early use of one GDMT class may decrease key adverse events to enable other drug classes—for example, SGLT2 inhibitors decrease hyperkalemia risk, slow kidney disease progression, and decrease risk of MRA discontinuation 3

Common Pitfalls

• Avoiding GDMT due to perceived adverse events: Most adverse events in HF patients cannot be clearly attributed to GDMT, and failure to initiate or withdrawal of GDMT may actually worsen symptoms 3

• Sequential rather than simultaneous initiation: Waiting to achieve target dosing of one medication before initiating the next substantially delays mortality benefit 1, 2

• Focusing on individual drug superiority: The question itself reflects a fundamental misunderstanding—the goal is comprehensive quadruple therapy, not selecting a "winner" among individual agents 3, 1