What is the initial approach for a patient with Heart Failure (HF) and moderately reduced Ejection Fraction (EF) using Guideline-Directed Medical Therapy (GDMT)?

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

Initiate all four foundational GDMT medication classes simultaneously at low doses—ARNI (sacubitril/valsartan preferred over ACE-I/ARB), beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor (dapagliflozin or empagliflozin)—then uptitrate every 1-2 weeks to target doses regardless of symptom severity. 1, 2

The Four-Pillar Simultaneous Initiation Strategy

Start all medications together at initial low doses rather than waiting to achieve target dosing of one 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% achieve target doses. 2

Specific Medication Regimen:

First-Line Combination:

• ARNI (Sacubitril/Valsartan): Start 24/26 mg twice daily, target 97/103 mg twice daily. This provides at least 20% mortality reduction superior to ACE-I/ARB. 1, 2 If switching from ACE-I, observe strict 36-hour washout to avoid angioedema. 2
• Beta-Blocker: Use only carvedilol (start 3.125 mg twice daily, target 25-50 mg twice daily), metoprolol succinate (start 12.5-25 mg daily, target 200 mg daily), or bisoprolol (start 1.25 mg daily, target 10 mg daily). These provide at least 20% mortality reduction. 1, 2
• MRA: Spironolactone 12.5-25 mg daily (target 25-50 mg daily) or eplerenone 25 mg daily (target 50 mg daily). Provides at least 20% mortality reduction. 3, 2 Use eplerenone if male gynecomastia concerns (5.7% higher rate with spironolactone). 2
• SGLT2 Inhibitor: Dapagliflozin 10 mg daily or empagliflozin 10 mg daily—no titration required. Benefits occur within weeks, independent of background therapy, with minimal blood pressure impact. 1, 2

Combined quadruple therapy reduces mortality by approximately 73% over 2 years and extends life expectancy by approximately 6 years compared to traditional dual therapy. 1, 2

Uptitration Protocol

Increase doses every 1-2 weeks until target doses achieved, using the forced-titration strategy from landmark trials. 3, 2 Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment. 1, 2 More frequent monitoring needed in elderly patients and those with chronic kidney disease. 2

Do not delay uptitration for:

• Asymptomatic hypotension or systolic BP 80-100 mmHg with adequate perfusion 3
• Modest creatinine elevation up to 30% above baseline 2
• Temporary symptoms of fatigue or weakness (usually resolve within days) 2

Managing Low Blood Pressure During Optimization

Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation. 3 Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (shock, pre-shock, organ hypoperfusion). 3

For patients with low BP but adequate perfusion, prioritize medications in this order: 3

1. SGLT2 inhibitors and MRAs first (minimal BP impact, may actually increase BP in low BP groups) 3
2. Beta-blockers if heart rate >60 bpm 3
3. ARNI/ACE-I/ARB at small incremental doses with close monitoring 3

Before reducing GDMT, stop non-heart failure medications causing hypotension (alpha-blockers for prostate, antidepressants) and address reversible causes (dehydration, infection, anemia). 3

Common Pitfalls to Avoid

Do not overreact to laboratory changes. Modest creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation. 2 Patients with adequate perfusion tolerate systolic BP 80-100 mmHg without harm. 2

Do not attribute all adverse events to GDMT. In landmark trials, 75-85% of patients reported adverse events, but rates were similar between active medication and placebo arms, reflecting the high-risk nature of heart failure itself rather than medication effects. 3 ACE-I causes 8.9% higher cough rate, beta-blockers cause 5.5% higher dizziness but 5% lower serious adverse events, MRAs cause 5.7% higher gynecomastia (spironolactone only), and SGLT2i cause 0.9% higher genital infection. 2

Do not discontinue GDMT in hospitalized patients except when hemodynamically unstable or contraindicated. 1, 2 In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting. 2

Monitoring Schedule

• 1-2 weeks after each dose increment: Blood pressure, renal function (creatinine, eGFR), electrolytes (potassium) 1, 2
• If eGFR >30 ml/min² and heart rate >60: Prioritize ARNI/ACE-I/ARB uptitration 3
• If eGFR >30 ml/min² and heart rate <60: Prioritize MRA optimization, consider ivabradine if beta-blocker not tolerated 3, 2

Implementation Strategies for Success

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 heart failure hospitalizations. 1, 4 Virtual peer-to-peer consultation and navigator-led remote optimization programs significantly increase GDMT initiation rates and dose achievement. 2, 5, 6

Refer early to heart failure specialists if persistent hypotension prevents GDMT initiation or titration despite optimization attempts. 3