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 used simultaneously for heart failure with reduced ejection fraction (HFrEF): (1) renin-angiotensin system (RAS) inhibitors or angiotensin receptor-neprilysin inhibitors (ARNI), (2) evidence-based beta-blockers, (3) mineralocorticoid receptor antagonists (MRAs), and (4) sodium-glucose cotransporter-2 (SGLT2) inhibitors. 1

The Four Pillars of GDMT Quad Therapy

1. RAS Inhibitors or ARNI

• ACE inhibitors (e.g., enalapril, lisinopril) or ARBs (e.g., losartan, valsartan) reduce mortality by 5-16% 2
• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors/ARBs, providing at least 20% reduction in mortality risk 2
• ARNI should replace ACE inhibitors/ARBs when tolerated, not be added to them 2

2. Evidence-Based Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol 2
• These provide at least 20% reduction in mortality risk 2
• Other beta-blockers (e.g., metoprolol tartrate, atenolol) are not considered GDMT 3

3. Mineralocorticoid Receptor Antagonists (MRAs)

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

4. SGLT2 Inhibitors

• Dapagliflozin or empagliflozin are the newest class added to HFrEF therapy 2
• Provide significant mortality benefits with a favorable safety profile 1
• Can be used regardless of diabetes status 1

Clinical Impact of Quad Therapy

Combined 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, 2
• Quad therapy also substantially reduces hospitalizations and improves quality of life 1, 4

Initiation Strategy: Simultaneous vs. Sequential

All four medications should be started simultaneously at low initial doses rather than waiting to achieve target dosing of one medication before initiating the next. 2

• The American College of Cardiology, American Heart Association, and Heart Failure Society of America recommend simultaneous initiation of all four foundational GDMT medications 2
• Rapid sequence or simultaneous initiation ensures patients benefit from proven medications and achieve large absolute risk reductions for adverse clinical outcomes 5
• There is no need to achieve target dosing before initiating the next medication 2

Uptitration Approach

After simultaneous initiation at low doses, uptitrate each medication at 1-2 week intervals until target doses are achieved. 2

• Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 2
• Temporary dose reductions should be followed by aggressive attempts to restore target doses 2
• Asymptomatic changes in vital signs and laboratory tests should not prevent uptitration 2

Common Barriers and How to Overcome Them

Low Blood Pressure

• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 2
• For systolic BP <90 mmHg, prioritize SGLT2 inhibitors and MRAs first (minimal BP impact), then selective β₁ receptor blockers, then low-dose ACEi/ARB or very low-dose ARNI 2

Renal Function Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ACEi/ARB/ARNI 2
• Temporary reduction or hold only if substantial renal deterioration occurs 2

Hyperkalemia

• SGLT2 inhibitors facilitate the use of MRAs by reducing the risk of severe hyperkalemia 1
• Close monitoring of potassium levels is essential, but mild elevations should not automatically lead to MRA discontinuation 2

Critical Implementation Gap

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, 2

• Most eligible patients are not prescribed an RAS inhibitor (1 in 4), beta-blocker (1 in 3), or MRA (2 in 3) 1
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 2
• Being seen in an HF clinic is independently associated with higher rates of GDMT initiation across all medication classes 3

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 2
• In-hospital initiation is a key strategy to improve GDMT utilization 1

Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 2
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 2

End-Stage CKD

• SGLT2 inhibitors remain the most strongly recommended therapy, with evidence of safety and efficacy extending to CKD stage 4 6
• Hydralazine and isosorbide dinitrate combination can be used for patients who cannot tolerate RAS inhibitors due to renal insufficiency 6