What is Guideline-Directed Medical Therapy (GDMT) quad therapy for a patient with heart failure with reduced ejection fraction?

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 for all patients with HFrEF: (1) ARNI (sacubitril/valsartan) or ACE inhibitor/ARB, (2) evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol only), (3) mineralocorticoid receptor antagonists (spironolactone or eplerenone), and (4) SGLT2 inhibitors (dapagliflozin or empagliflozin). 1, 2

The Four Pillars of Quad Therapy

Pillar 1: Renin-Angiotensin System Inhibition

• ARNI (sacubitril/valsartan) is strongly preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk and superior outcomes compared to enalapril 1, 2, 3
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 1, 4
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 2, 4
• If ARNI is not tolerated or available, use ACE inhibitors or ARBs and uptitrate to target doses 2, 3

Pillar 2: Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol—do not substitute with other beta-blockers 1, 2, 3
• These provide at least 20% reduction in mortality risk 1, 2, 3
• Start at low doses and uptitrate to target doses every 1-2 weeks 1, 2

Pillar 3: Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily), uptitrating to target doses 1, 2, 5
• These provide at least 20% reduction in mortality risk 1, 2, 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone 2, 3
• Monitor potassium and creatinine closely, especially during uptitration 1, 2

Pillar 4: SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—these are the newest class with significant mortality benefits 1, 2, 3
• Major advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks of initiation, independent of background therapy 2, 3
• Safe in moderate kidney dysfunction with eGFR ≥30 mL/min/1.73m² for empagliflozin and ≥20 mL/min/1.73m² for dapagliflozin 3

Critical Implementation Strategy: Simultaneous Initiation

Start all four medication classes simultaneously at low initial doses rather than waiting to achieve target dosing of one before initiating the next. 1, 2, 3 This approach directly addresses the massive treatment gap where less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications. 6, 2

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved, checking blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2
• Prioritize ARNI/ACE inhibitor/ARB uptitration if eGFR >30 mL/min/1.73m² and heart rate >60 bpm 2
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease 2, 3

Mortality Benefit

Quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment and extends life expectancy by approximately 6 years compared to traditional dual therapy (ACE inhibitor and beta-blocker). 6, 1, 2, 3

Managing Common Barriers to Uptitration

Low Blood Pressure

• Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation 2, 3
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 2, 3
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria) 2
• If blood pressure is low but perfusion adequate, prioritize medications in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then beta-blockers, then ARNI/ACE inhibitor/ARB 2, 3

Renal Function Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB 2, 3
• Temporary reduction or hold only if substantial renal deterioration occurs 2

Hyperkalemia

• Monitor potassium closely with MRA initiation and uptitration 2
• Adjust MRA dose or consider potassium binders if needed rather than discontinuing therapy 2

Temporary Symptoms

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT 2, 3

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2, 3
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 2, 3
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 2

Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen 2, 3
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration 2, 3

Common Pitfalls to Avoid

• Do not wait to achieve target dosing of one medication before initiating the next—this delays life-saving therapy 2, 3
• Do not overreact to laboratory changes—modest creatinine elevation (up to 30% above baseline) is acceptable 2, 3
• Do not withhold GDMT for asymptomatic hypotension if perfusion is adequate 2, 3
• Do not use non-evidence-based beta-blockers as substitutes for carvedilol, metoprolol succinate, or bisoprolol 1, 2, 3

Additional Therapies

• Add loop diuretics only if fluid overload is present—they are for volume management but provide no mortality benefit 2, 3
• Titrate based on symptoms and volume status, not as routine therapy 2, 3