What is the management for patients with Heart Failure with Reduced Ejection Fraction (HFrEF), including Guideline-Directed Medical Therapy (GDMT) and anticoagulation?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

Foundational Quadruple Therapy (GDMT)

All patients with HFrEF should be started on four medication classes simultaneously at low doses and uptitrated every 1-2 weeks to target doses, regardless of symptom severity. 1, 2 This 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 Pillars of GDMT

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - PREFERRED

• Sacubitril/valsartan is preferred over ACE inhibitors or ARBs, providing at least 20% reduction in mortality risk with superior outcomes compared to enalapril. 1, 2
• Starting dose: 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. 2, 3
• If ARNI is not tolerated or available, use ACE inhibitors (enalapril, lisinopril) or ARBs and uptitrate to target doses. 4, 2

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, 2
• Selective β₁ receptor blockers (metoprolol succinate, bisoprolol) may be preferred in patients with low blood pressure due to lesser BP-lowering effect than non-selective beta-blockers. 4
• Carvedilol is preferred if refractory hypertension is present 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. 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. 1, 2
• Safe in moderate kidney dysfunction: eGFR ≥30 ml/min/1.73 m² for empagliflozin and ≥20 ml/min/1.73 m² for dapagliflozin. 1

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 Less than one-quarter of eligible patients currently receive all medications concurrently, and only 1% receive target doses of all medications. 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
• Uptitrate one drug at a time using small increments. 4

Managing Low Blood Pressure During GDMT Optimization

Asymptomatic or mildly symptomatic low blood pressure should never prompt GDMT reduction or cessation. 4, 2 Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 4, 2

When to Reduce or Stop GDMT

• Only reduce or stop GDMT if systolic BP <80 mmHg or low BP with major symptoms (confusion, syncope, oliguria). 2

Medication Prioritization in Low BP Patients

If blood pressure is low but perfusion adequate, prioritize medications in this specific order: 4, 2

1. First: SGLT2 inhibitors and MRAs (minimal BP impact, rapid beneficial effect). 4
2. Second: Beta-blockers (if heart rate >70 bpm), preferably selective β₁ receptor blockers. 4
3. Third: ARNI/ACE inhibitor/ARB at low dose (sacubitril/valsartan 25 mg or 50 mg twice daily, or low-dose ACE inhibitor). 4

Alternative Strategies for Low BP

• If beta-blockers are not well tolerated hemodynamically, ivabradine may be a viable alternative, either alone or with low-dose beta-blockers, as it helps facilitate their titration. 4
• In atrial fibrillation with uncontrolled heart rate, digoxin may be used. 4

Addressing Reversible Causes

• Stop unnecessary cardiac medications (non-class I HFrEF antihypertensives, antiarrhythmics). 4
• Coordinate selection of appropriate alternatives with lesser BP-lowering effect for non-cardiac medications (medications for prostate hypertrophy, antidepressants). 4
• Adjust diuretics according to volume status—overdiuresis may result in lower BP. 4

Managing Common Barriers to Uptitration

Renal Function

• 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, 2

Anticoagulation in HFrEF

Anticoagulation is NOT routinely recommended for HFrEF patients in sinus rhythm. The guidelines provided do not support routine anticoagulation based solely on reduced ejection fraction.

When to Anticoagulate

• Atrial fibrillation: Use CHA₂DS₂-VASc score to guide anticoagulation decisions (score ≥2 in men, ≥3 in women warrants anticoagulation).
• Left ventricular thrombus: Anticoagulation is indicated for documented LV thrombus.
• Other standard indications: Venous thromboembolism, mechanical heart valves, or other guideline-based indications.

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. 2
• In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 1
• Initial IV loop diuretic dose should equal or exceed chronic oral daily dose, titrating 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 with NYHA Class III-IV

• Add hydralazine/isosorbide dinitrate to quadruple therapy. 1

Additional Therapies Beyond Quadruple GDMT

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 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

Ivabradine

• Consider if heart rate remains >70 bpm despite beta-blocker therapy in patients with sinus rhythm. 4
• May be used as alternative if beta-blockers are not hemodynamically tolerated. 4

Device Therapies

Cardiac Resynchronization Therapy (CRT)

• Consider in specific conditions to facilitate optimization of GDMT. 4

Transcatheter Edge-to-Edge Repair (TEER)

• May be appropriate in specific conditions to facilitate optimization of GDMT. 4

Implementation Strategies

Multidisciplinary Care

• 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, 2

Specialty Referral

• Referral to HF specialty care maximizes GDMT optimization in newly diagnosed HFrEF patients. 1, 2
• In persistent hypotension with inability to initiate or titrate GDMT, refer early to HF specialist or advanced therapy programs. 4

Digital Solutions

• Best practice advisories, electronic health record-based interventions, and telehealth visits increase GDMT prescription rates. 1, 2

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 is acceptable. 1, 2
• Do not discontinue GDMT for asymptomatic low blood pressure—patients with adequate perfusion tolerate systolic BP 80-100 mmHg. 4, 2
• Do not use non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol have proven mortality benefit. 1, 2
• Do not use non-dihydropyridine calcium channel blockers, moxonidine, or alpha-adrenergic blockers—they may increase risk of worsening heart failure. 1
• Physicians in other subspecialties should consult with the HF team before reducing or withholding HFrEF medications due to perception of 'low BP' readings. 4

Follow-up and Monitoring

• Early follow-up (within 7-14 days) after medication adjustments is recommended. 1
• Monitor for changes in volume status and blood pressure, renal function and electrolytes, and symptoms of worsening heart failure. 1
• When BP improves, always consider reinitiation or rechallenge of drugs based on better tolerated first. 4
• Strive to achieve optimal therapy. 4