What is Guideline-Directed Medical Therapy (GDMT) quad therapy?

GDMT Quad Therapy for Heart Failure with Reduced Ejection Fraction

GDMT quad therapy consists of four foundational medication classes that must be initiated simultaneously at low doses in all eligible patients with heart failure with reduced ejection fraction (HFrEF): (1) ACE inhibitors/ARBs or preferably ARNI (sacubitril/valsartan), (2) evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol), (3) mineralocorticoid receptor antagonists (spironolactone or eplerenone), and (4) SGLT2 inhibitors (dapagliflozin or empagliflozin). 1, 2

The Four Pillars and Their Individual Impact

Pillar 1: RAS Inhibition or ARNI

• ACE inhibitors or ARBs reduce mortality by 5-16% in HFrEF patients 2
• ARNI (sacubitril/valsartan) is strongly preferred over ACE inhibitors/ARBs, providing at least 20% reduction in mortality risk 2, 3

Pillar 2: Evidence-Based Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol 2, 3
• These provide at least 20% reduction in mortality risk 2

Pillar 3: Mineralocorticoid Receptor Antagonists

• Spironolactone or eplerenone provide at least 20% reduction in mortality risk 2, 3
• Start at low doses (spironolactone 12.5-25 mg daily or eplerenone 25 mg daily) with close monitoring of potassium and creatinine 3

Pillar 4: SGLT2 Inhibitors

• Dapagliflozin or empagliflozin represent the newest class with significant mortality benefits 2, 3
• These have minimal blood pressure impact, making them ideal for early initiation 3

The Dramatic Combined Effect

The mortality benefit is multiplicative, not additive:

• Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment 1, 2
• 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, 3

Critical Implementation Strategy: Simultaneous Initiation

Start all four medications simultaneously at low initial doses rather than sequential titration. 2, 3 This represents a paradigm shift from older approaches that waited to achieve target dosing of one medication before initiating the next.

The forced-titration protocol:

• Initiate all four classes at low doses simultaneously or in rapid sequence 2, 3
• Uptitrate every 1-2 weeks until target doses are achieved 3
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 2, 3
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 3

Common Pitfalls to Avoid

Do not withhold therapy for asymptomatic laboratory changes:

• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt discontinuation 3
• Patients with adequate perfusion can tolerate systolic blood pressure 80-100 mmHg 3
• Asymptomatic or mildly symptomatic low blood pressure should not prevent GDMT initiation 3

Do not prescribe subtarget doses without following forced-titration strategies 2—only 1% of patients currently receive target doses of all medications, representing a massive treatment gap 3

Do not delay initiation in hospitalized patients:

• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 2, 3
• Continue GDMT in hospitalized patients except when hemodynamically unstable 2, 3

Special Clinical Scenarios

For patients with low systolic blood pressure (<90 mmHg) but adequate perfusion:

• Prioritize SGLT2 inhibitors and MRAs first (minimal BP impact) 3
• Add selective β₁ receptor blockers next 3
• Use low-dose ACEi/ARB or very low-dose ARNI last 3

For patients with chronic kidney disease or elderly patients:

• More frequent monitoring is needed during uptitration 3
• Do not withhold therapy based on age or renal function alone if patient is otherwise eligible 3

The Current Treatment Gap

Despite overwhelming evidence, less than one-quarter of eligible patients currently receive all three medications concurrently (before SGLT2 inhibitors became standard), and only 1% receive target doses of all medications 1, 3. This persistent underutilization has remained virtually unchanged over the past decade despite quality improvement initiatives and strong guideline recommendations 1.