What is the guideline-directed management (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 initiated on quadruple therapy consisting of four medication classes simultaneously: ARNI (or ACEi/ARB), evidence-based beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor, started at low doses and uptitrated every 1-2 weeks to target doses. 1, 2

The Four Pillars of HFrEF Treatment

1. Renin-Angiotensin System Inhibition

• ARNI (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs, providing at least 20% mortality reduction compared to 5-16% for ACEi/ARBs 2, 3
• Starting dose: 49/51 mg twice daily, target dose: 97/103 mg twice daily 4
• Critical safety requirement: 36-hour washout period when switching from ACE inhibitor to ARNI to avoid angioedema 1, 4
• If ARNI is not tolerated or available, use ACE inhibitor or ARB (candesartan or valsartan if intolerant to ACEi due to cough) 3

2. Evidence-Based Beta-Blockers

• Use only carvedilol, metoprolol succinate, or bisoprolol - these specific agents provide at least 20% mortality reduction 2, 3
• Other beta-blockers lack mortality benefit in HFrEF 3

3. Mineralocorticoid Receptor Antagonists

• Spironolactone or eplerenone provide at least 20% mortality reduction 2
• Start at low doses: spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 2
• Eplerenone avoids the 5.7% higher rate of gynecomastia seen with spironolactone 2
• Contraindications: serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women, serum potassium ≥5.0 mEq/L 3

4. SGLT2 Inhibitors (Newest Class)

• Dapagliflozin or empagliflozin provide significant mortality benefits regardless of diabetes status 1, 2, 5
• Major advantages: no blood pressure, heart rate, or potassium effects; no dose titration required; benefits occur within weeks 2
• Only 0.9% higher rate of genital infection compared to placebo 2

Initiation Strategy: Simultaneous vs Sequential

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 critical because:

• Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment 2
• Transitioning from traditional dual therapy to quadruple therapy extends life expectancy by approximately 6 years 2
• Currently, less than one-quarter of eligible patients receive all medications concurrently, and only 1% receive target doses of all medications 2

Uptitration Protocol

Uptitrate every 1-2 weeks until target doses are achieved, using a forced-titration approach as used in landmark trials. 2, 6

Monitoring Schedule

• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 2
• More frequent monitoring needed in elderly patients and those with chronic kidney disease 2
• Early follow-up within 7-14 days after medication adjustments 6

Common Barriers and How to Overcome Them

Low Blood Pressure (Systolic 80-100 mmHg)

• Do not withhold GDMT if patient has adequate organ perfusion 2
• Asymptomatic or mildly symptomatic low blood pressure should not prevent uptitration 2
• Prioritize SGLT2 inhibitors and MRAs first (minimal BP impact), then selective β₁ receptor blockers, then low-dose ACEi/ARB or very low-dose ARNI 2

Modest Creatinine Elevation

• Increases up to 30% above baseline are acceptable and should not prompt discontinuation of ACEi/ARB/ARNI 2
• Only reduce or hold temporarily if substantial renal deterioration occurs 2

Hyperkalemia

• Monitor potassium closely with MRA use 2
• Serum potassium must be <5.0 mEq/L before initiating MRA 3

Temporary Symptoms

• Fatigue and weakness with dose increases usually resolve within days 2
• Do not prematurely discontinue GDMT for transient symptoms 2

Special Clinical Scenarios

Hospitalized Patients

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

Improved Ejection Fraction (HFimpEF)

• 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, 6

Low Ejection Fraction with Pulmonary Hypertension

• Optimize GDMT to target doses - this is the most effective approach for pulmonary hypertension secondary to left heart disease 6
• Optimize diuretic therapy to reduce pulmonary congestion, consider combination diuretic therapy (loop + thiazide) for diuretic resistance 6
• If beta-blockers not hemodynamically tolerated, consider ivabradine as alternative for heart rate control 6

Additional Therapies for Specific Subgroups

Adjunctive Medications (Beyond Core Four)

• Hydralazine/isosorbide dinitrate: Add in self-described African Americans with class II-IV HF already on diuretics, ACE inhibitors, and beta-blockers 3
• Ivabradine: Consider if heart rate ≥70 bpm despite beta-blocker optimization, or if beta-blockers not tolerated 3, 5
• Vericiguat: Reduces HF hospitalization in high-risk patients with recent decompensation 5
• Loop diuretics: Add only if fluid overload is present 2, 3

Device Therapies

• Cardiac resynchronization therapy (CRT) in patients with interventricular dyssynchrony (QRS ≥150 ms) 7, 5
• Implantable cardioverter defibrillators (ICDs) in patients with LVEF ≤35% despite optimal medical therapy, particularly ischemic etiology 7, 5
• Transcatheter mitral valve repair in patients with severe secondary mitral regurgitation 5

Implementation Strategies to Improve GDMT Utilization

• Nurse-led titration programs reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92) 2
• Pharmacist involvement improves GDMT adherence and dosing 2
• Virtual peer-to-peer consultation increases GDMT initiation rates 2
• Digital solutions (best practice advisories, EHR-based interventions, telehealth visits) increase GDMT prescription 2
• Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization 2

Critical Pitfalls to Avoid

1. Sequential rather than simultaneous initiation - delays full benefit and reduces likelihood of achieving quadruple therapy 2
2. Overreacting to asymptomatic laboratory changes - modest creatinine elevation acceptable, low BP with adequate perfusion tolerable 2
3. Premature discontinuation for temporary symptoms - fatigue and weakness typically resolve within days 2
4. Using non-evidence-based beta-blockers - only carvedilol, metoprolol succinate, or bisoprolol have mortality benefit 2, 3
5. Discontinuing GDMT when EF improves - leads to clinical deterioration 2, 6
6. Deferring GDMT initiation to outpatient setting in hospitalized patients - substantially reduces post-discharge medication use 2