Management of Heart Failure with Reduced Ejection Fraction
All patients with HFrEF should receive quadruple guideline-directed medical therapy (GDMT) consisting of an ARNI (sacubitril/valsartan), evidence-based beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor, titrated to target doses as tolerated, as this combination provides the greatest mortality and morbidity benefit. 1, 2, 3
Initial Pharmacological Approach
First-Line Quadruple Therapy Components
Start all four medication classes simultaneously or in rapid sequence:
ARNI (Sacubitril/Valsartan): Start at 49/51 mg twice daily, titrate to target dose of 97/103 mg twice daily after 2-4 weeks 4, 3. This replaces ACE inhibitors or ARBs and provides superior mortality reduction 5, 6.
Evidence-Based Beta-Blockers: Use carvedilol, metoprolol succinate, or bisoprolol at low doses initially, uptitrate to target doses over 2-4 weeks 1, 3. These reduce mortality by at least 20% and decrease sudden death risk 2.
Mineralocorticoid Receptor Antagonists (MRAs): Spironolactone or eplerenone reduce mortality and sudden death risk by 23% 2, 3. Essential when LVEF <35% or symptoms persist (NYHA II-IV) 5.
SGLT2 Inhibitors: Dapagliflozin or empagliflozin reduce HF hospitalization and death with minimal blood pressure effects 1, 2, 3. These should be prioritized as they have the least impact on BP while providing mortality benefits 7.
Critical Timing Considerations
Allow a 36-hour washout period when switching from ACE inhibitors to sacubitril/valsartan to avoid angioedema risk 4.
In hospitalized patients with acute decompensated HF, continue GDMT during admission unless hemodynamic instability or contraindications exist 1. Initiate or optimize GDMT in stable patients prior to discharge 1, 8.
Managing Low Blood Pressure During Optimization
When to Proceed Despite Low BP
Do not withhold or reduce GDMT for asymptomatic or mildly symptomatic low blood pressure, as mortality benefits outweigh risks 1, 2. Low BP alone (even SBP <100 mmHg) should not automatically prevent medication use 2, 9.
Sequencing Drug Adjustments in Symptomatic Hypotension
If severe symptomatic hypotension (SBP <80 mmHg) persists after addressing reversible causes:
First, discontinue non-cardiac medications with BP-lowering effects (alpha-blockers for prostate, antidepressants) 1.
If heart rate >70 bpm: Reduce ACEi/ARB/ARNI first 7.
If heart rate <60 bpm: Reduce beta-blocker first 7.
Maintain SGLT2 inhibitors and MRAs as they have minimal BP effects 1, 7.
Patients recovering from acute HF with lower baseline BP require more gradual uptitration and closer post-discharge monitoring 1.
Additional Therapies for Specific Scenarios
Symptom Management
Loop diuretics for congestion relief: Titrate to achieve euvolemia, monitoring daily weights and clinical signs 1, 3. When diuresis is inadequate, intensify with higher doses, add a second diuretic (metolazone, IV chlorothiazide), or use continuous infusion 1.
Heart Rate Management
Ivabradine if heart rate remains >70 bpm despite maximally tolerated beta-blocker in symptomatic patients 5, 3.
Additional Medications for Persistent Symptoms
Vericiguat or omecamtiv mecarbil may be considered for patients with worsening HF despite optimal GDMT, particularly those requiring recent hospitalization 6, 9.
Hydralazine/nitrates for African American patients or those intolerant to ARNI/ACEi/ARB 3.
Iron Deficiency
Intravenous iron replacement when ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20%, as the threshold for substitution is higher than in patients without HF 5, 3.
Device Therapy Indications
Implantable cardioverter-defibrillator (ICD): Strongly recommended for patients with LVEF ≤35% despite ≥3 months of optimal medical therapy, expected survival >1 year with good functional status 2.
Cardiac resynchronization therapy (CRT): Consider for symptomatic HF patients with LVEF ≤35% despite GDMT and QRS duration ≥150 ms with LBBB morphology 2.
Monitoring Strategy
Close follow-up within 1-2 weeks after medication changes or hospital discharge 1, 7. Monitor:
- Blood pressure (supine and standing) 1
- Heart rate 1
- Daily weights at same time each day 1
- Serum electrolytes, creatinine, and BUN during IV diuretic use or active GDMT titration 1
- NT-proBNP levels to guide therapy 1
Critical Pitfalls to Avoid
Never discontinue GDMT due to asymptomatic low BP readings - the mortality benefits far outweigh risks 1, 2. Physicians in other subspecialties should consult the HF team before reducing or withholding HFrEF medications 1.
Avoid premature discontinuation of medications during acute decompensation - poor outcomes associated with side effects often stem from stopping therapy rather than the side effects themselves 1.
Do not delay ICD/CRT evaluation in eligible patients, as timely implementation reduces mortality 2.
Avoid underutilization of GDMT despite proven benefits - clinical inertia remains a major barrier to optimal outcomes 1, 2.
Special Clinical Conditions Requiring Caution
Exercise particular caution with low BP in patients with:
- Significant peripheral vascular disease with non-healing ulcers 1
- Bilateral untreated carotid stenosis 1
- Recent cerebrovascular accident 1
- Bowel ischemia or abdominal angina 1
- End-stage renal disease on dialysis 1
- Autonomic dysfunction 1
These scenarios require multidisciplinary team management 1.
Advanced Therapy Referral
Refer early to HF specialist or advanced therapy programs when:
- Persistent hypotension prevents GDMT optimization 1, 7
- LVEF remains severely reduced despite optimal therapy 2
- Recurrent hospitalizations despite maximal medical management 2
Consider heart transplantation evaluation for patients with extremely low EF and poor prognosis despite comprehensive therapy 2.