What is the Guideline-Directed Medical Therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF)?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF should be started on four foundational medication classes simultaneously at low doses—ARNI (preferably) or ACE inhibitor/ARB, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—then uptitrated every 1-2 weeks to target doses regardless of symptom severity. 1, 2

The Four Pillars of GDMT for HFrEF

1. Renin-Angiotensin System Inhibition

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk and superior outcomes compared to enalapril. 2, 3
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily. 4, 5
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema. 2, 5
• If ARNI is not tolerated or available, use ACE inhibitors or ARBs and uptitrate to target doses shown effective in trials. 2

2. Beta-Blockers

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

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Use spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily), uptitrating to target doses. 2, 4
• These provide at least 20% reduction in mortality risk. 2, 3
• Eplerenone avoids the 5.7% higher rate of male gynecomastia seen with spironolactone. 2
• Monitor potassium and creatinine closely, especially during uptitration. 2

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—these are the newest class with significant mortality benefits. 1, 2
• 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
• This makes SGLT2 inhibitors ideal for patients with low blood pressure or electrolyte concerns. 2

Combined Therapy Impact

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). 2, 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 is supported by the 2022 ACC/AHA/HFSA guidelines and 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. 2, 3

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. 2, 4, 3
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease. 2
• Prioritize ARNI/ACE inhibitor/ARB uptitration if eGFR >30 mL/min/1.73m² and heart rate >60 bpm. 4

Managing Common Barriers to Uptitration

Low Blood Pressure

• Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation. 2, 4
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 2
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria). 4
• 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, 4

Renal Function

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB. 2
• 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. 4

Fatigue and Weakness

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

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated. 2, 3
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion. 3
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 2
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrating based on urine output and congestion symptoms. 2

Patients with Improved Ejection Fraction

• Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen. 1, 2
• Discontinuation of HFrEF medications after EF improvement may lead to clinical deterioration. 2

Additional Therapies

Loop Diuretics

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

Vericiguat

• Consider vericiguat for higher-risk patients with worsening HFrEF (LVEF <45%, NYHA class II-IV, elevated natriuretic peptides, recent HF hospitalization or IV diuretic therapy) who remain symptomatic despite GDMT. 1
• Vericiguat reduced the primary outcome of cardiovascular death or HF hospitalization by 10% (HR 0.90, P=0.019) in the VICTORIA trial. 1
• Patients in the highest quartile of NT-proBNP (>5314 pg/mL) did not benefit from vericiguat. 1

Implementation Strategies to Improve GDMT Use

• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration, reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92), and reduce HF hospitalizations. 2, 3
• Nurse-led titration programs are effective for achieving target doses. 2
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients. 2, 6
• Being seen in an HF clinic is independently associated with initiation of GDMT across all medication classes (HR 1.54-2.49 depending on drug class). 6
• Digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates. 2

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
• Do not discontinue GDMT for asymptomatic low blood pressure—only intervene if systolic BP <80 mmHg or symptomatic hypotension with end-organ hypoperfusion. 2, 4
• Do not use non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol have proven mortality benefit. 2, 3
• Do not forget the 36-hour washout period when switching from ACE inhibitor to ARNI—this prevents life-threatening angioedema. 2, 5