What is the recommended Guideline-Directed Medical Therapy (GDMT) for a patient with 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

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
• Start sacubitril/valsartan at 24/26 mg or 49/51 mg twice daily, targeting 97/103 mg twice daily 2, 3
• Critical safety requirement: When switching from an ACE inhibitor to ARNI, observe a strict 36-hour washout period to avoid angioedema 1, 2
• If ARNI is not tolerated or available, use ACE inhibitors or ARBs and uptitrate to target doses shown effective in trials 4, 1

2. Evidence-Based Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate, or bisoprolol—do not substitute with other beta-blockers 1, 2
• These provide at least 20% reduction in mortality risk 1
• Start at low doses and uptitrate to target doses every 1-2 weeks 1, 2
• If refractory hypertension is present, carvedilol is preferred due to its combined α1-β1-β2-blocking properties 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

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

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—these are the newest class with significant mortality benefits 4, 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 1, 2
• Safe in moderate kidney dysfunction with eGFR ≥30 ml/min/1.73 m² for empagliflozin and ≥20 ml/min/1.73 m² for dapagliflozin 1

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). 1, 2

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 This approach is supported by the American College of Cardiology, American Heart Association, and Heart Failure Society of America 1. Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications, representing a massive treatment gap that simultaneous initiation directly addresses 1.

Uptitration Protocol

• Uptitrate every 1-2 weeks until target doses are achieved 1, 2
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease 1

Managing Common Barriers to Uptitration

Low Blood Pressure

• Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation 1, 2
• Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg 1, 2
• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria) 1, 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 1, 2

Renal Function Changes

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation of ARNI/ACE inhibitor/ARB 1, 2
• Temporary reduction or hold only if substantial renal deterioration occurs 1
• Renal dysfunction was a frequent barrier to GDMT optimization in octogenarians and nonagenarians 5

Hyperkalemia

• Monitor potassium closely with MRA initiation and uptitration 1, 2
• Adjust MRA dose or consider potassium binders if needed rather than discontinuing therapy 2
• Hyperkalemia was identified as a common barrier to GDMT in elderly patients 5

Temporary Side Effects

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days—do not prematurely discontinue GDMT 1, 2

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 1, 2
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 1, 2
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting 1, 2
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrated based on urine output and congestion symptoms 1

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 1, 2

Self-Identified Black Patients

• For patients with NYHA Class III-IV symptoms, add hydralazine/isosorbide dinitrate to quadruple therapy 1

Additional Therapies

Loop Diuretics

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

Vericiguat

• Consider 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 2
• Vericiguat reduced the primary outcome of cardiovascular death or HF hospitalization by 10% (HR 0.90, P=0.019) 2
• Patients in the highest quartile of NT-proBNP (>5314 pg/mL) did not benefit from vericiguat 2

Implementation Strategies to Improve GDMT Use

• Multidisciplinary care teams including pharmacists and nurses improve GDMT titration and reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92) 1, 2
• Nurse-led titration programs are effective for achieving target doses and demonstrated significant improvement in ejection fraction from 21.8% to 36.2% with reduction in heart failure hospitalizations 2, 6
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients 1
• Digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates 1

Critical Pitfalls to Avoid

• Do not wait to achieve target dosing of one medication before initiating the next—this delays life-saving therapy 1, 2
• Do not overreact to laboratory changes—modest creatinine elevation (up to 30% above baseline) is acceptable 1, 2
• Do not use non-evidence-based beta-blockers as substitutes for carvedilol, metoprolol succinate, or bisoprolol 1, 2
• Do not use non-dihydropyridine calcium channel blockers, moxonidine, or alpha-adrenergic blockers in HFrEF patients, as they may increase the risk of worsening heart failure 1
• Adverse events are common in heart failure patients, but most are not attributable to GDMT medications and should not prevent appropriate therapy initiation 1