Is there a stepwise approach to adding Guideline-Directed Medical Therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF)?

Stepwise Approach to Adding GDMT for HFrEF

The current guideline-recommended approach is NOT stepwise—all four foundational GDMT medication classes (ARNI/ACE inhibitor/ARB, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor) should be initiated simultaneously at low doses, then uptitrated every 1-2 weeks to target doses. 1, 2

The Paradigm Shift: Simultaneous vs Sequential Initiation

The traditional stepwise approach has been abandoned because:

• Simultaneous initiation of all four classes at low doses is now the standard of care rather than waiting to achieve target dosing of one medication before initiating the next 1, 2
• This approach directly addresses the massive treatment gap where less than one-quarter of eligible patients receive all medications concurrently, and only 1% receive target doses of all medications 1
• 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 1, 2

The Four Foundational Medication Classes

1. ARNI (Preferred) or ACE Inhibitor/ARB

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

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
• These provide at least 20% reduction in mortality risk 1, 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 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 2

4. SGLT2 Inhibitors

• Use dapagliflozin or empagliflozin—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 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

Practical Implementation Algorithm

Step 1: Initial Assessment and Simultaneous Initiation

• Start all four medication classes simultaneously at low initial doses after confirming HFrEF diagnosis (EF ≤40%) 1, 2
• For hospitalized patients, 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 to outpatient setting 1

Step 2: 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
• Prioritize ARNI/ACE inhibitor/ARB uptitration if eGFR >30 mL/min/1.73 m² and heart rate >60 bpm 2

Step 3: 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) 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, 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

Fatigue and Weakness

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

Special Clinical Scenarios

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 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

Higher-Risk Patients

• 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 2
• Vericiguat reduced cardiovascular death or HF hospitalization by 10% (HR 0.90, P=0.019) 2

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

Common 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
• Do not discontinue GDMT during or after heart failure hospitalization without clear contraindications, as de-escalation/discontinuation after HFH is associated with increased risk of all-cause mortality with hazard ratios ranging from 2.94 to 4.81 3
• Do not use calcium channel blockers as they are not part of GDMT for HFrEF and may worsen outcomes 1

Implementation Strategies

• 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 1
• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients 1, 4
• Digital solutions such as best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates 1