Initial Management of Heart Failure with Reduced Ejection Fraction
For patients with heart failure and reduced ejection fraction (HFrEF), immediately initiate four foundational medication classes simultaneously: SGLT2 inhibitors, ACE inhibitors (or ARNI/ARB), beta-blockers, and mineralocorticoid receptor antagonists (MRAs), along with diuretics if fluid retention is present. 1, 2
Core Pharmacotherapy: The Four-Pillar Approach
Start All Four Classes Together
The 2022 AHA/ACC/HFSA guidelines fundamentally changed HF management by recommending simultaneous initiation of all four medication classes rather than sequential addition. 1 This approach maximizes early mortality benefit and should be implemented at initial diagnosis of symptomatic HFrEF (Stage C). 2
The four pillars are:
SGLT2 inhibitors (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) - Start immediately in all patients with eGFR >20 mL/min/1.73 m². 2, 3 These provide rapid mortality benefit with minimal blood pressure effects, making them ideal first-line agents. 2, 3
ACE inhibitors or ARNI - ACE inhibitors remain the standard for symptomatic patients and reduce morbidity and mortality. 1 ARNI (sacubitril/valsartan) is preferred over ACE inhibitors for NYHA class II-III patients as it further reduces morbidity and mortality. 1, 4, 5
Beta-blockers (bisoprolol, carvedilol, or sustained-release metoprolol succinate) - Use in all patients with stable HFrEF NYHA class II-IV to reduce mortality. 1, 2, 5
Mineralocorticoid receptor antagonists (spironolactone 12.5-25 mg or eplerenone 25 mg daily) - Indicated for NYHA class II-IV with ejection fraction ≤35% if eGFR >30 mL/min/1.73 m². 1, 2, 6
Diuretics for Fluid Management
Loop diuretics should be used in all patients with evidence or history of fluid retention. 1, 3 Adjust doses based on volume status and monitor for electrolyte abnormalities and dehydration. 1 Reduce diuretic dose when initiating ACE inhibitors to prevent hypotension. 3
Medication Initiation Strategy Based on Blood Pressure
For Patients with Low Blood Pressure but Adequate Perfusion
Start SGLT2 inhibitor and MRA first, as neither significantly lowers blood pressure. 2 Then add low-dose beta-blocker if heart rate >70 bpm, followed by low-dose ACE inhibitor/ARNI with gradual uptitration. 2, 3
For Patients with Normal Blood Pressure
Initiate SGLT2 inhibitor and MRA simultaneously, then add either low-dose beta-blocker or low-dose ACE inhibitor/ARNI. 2, 3 Uptitrate one drug at a time using small increments every 1-2 weeks. 2
Target Dosing
Start all medications at low doses and titrate gradually to target doses proven effective in clinical trials. 2, 3, 5 Real-world data shows only 17-29% of patients achieve target ACE inhibitor/ARB doses and only 13-28% achieve target beta-blocker doses, with just 1% reaching target doses of all drugs simultaneously. 2 This represents a critical treatment gap that must be addressed through systematic uptitration.
Critical Monitoring Parameters
Baseline Laboratory Assessment
Obtain complete blood count, urinalysis, fasting lipids, liver function, electrolytes, BUN, creatinine, glucose, and TSH before initiating therapy. 2
Post-Initiation Monitoring
Check blood pressure, heart rate, renal function, and electrolytes 1-2 weeks after each medication initiation or dose increment. 2, 3 This close monitoring is essential for safe uptitration and is associated with improved patient outcomes. 2
For potassium-sparing diuretics (MRAs), check potassium and creatinine after 5-7 days and recheck every 5-7 days until stable. 2 Monitor for hyperkalemia (K+ >5.0 mEq/L) and renal insufficiency. 1, 6
Common Pitfalls and How to Avoid Them
Never Discontinue GDMT for Asymptomatic Hypotension
Do not stop guideline-directed medical therapy for asymptomatic or mildly symptomatic low blood pressure, as this compromises long-term outcomes. 2 Patients can tolerate systolic blood pressures in the 90s mmHg range if adequately perfused.
Avoid NSAIDs
NSAIDs interfere with ACE inhibitor efficacy and worsen renal function. 2 Counsel patients explicitly to avoid over-the-counter NSAIDs.
Don't Over-Diurese Before Starting ACE Inhibitors
Excessive diuresis before initiating ACE inhibitors can precipitate hypotension. 2 Reduce diuretic dose when starting renin-angiotensin system inhibitors. 3
Thiazide Limitations
Don't use thiazides if GFR <30 mL/min unless combined synergistically with loop diuretics. 2
De-escalation During Hospitalization
GDMT doses are frequently reduced during non-cardiovascular hospitalizations, and ACE inhibitor/ARB de-escalation is associated with reduced post-discharge survival. 7 Post-discharge care plans must include robust plans to re-escalate GDMT. 7
Special Populations and Adjustments
Renal Dysfunction
For eGFR <30 mL/min/1.73 m², reduce or avoid MRAs and adjust renin-angiotensin system inhibitor dosing. 3 SGLT2 inhibitors should not be started if eGFR <30 mL/min/1.73 m², though they may be continued if already established. 3
Hyperkalemia Management
For potassium >5.0 mEq/L, reduce MRA dose first before adjusting other GDMT. 3 Serum potassium should be <5.0 mEq/L before initiating aldosterone antagonists. 6, 5
African American Patients
Add isosorbide dinitrate plus hydralazine in self-described African American patients with NYHA class II-IV HF already on diuretics, ACE inhibitors, and beta-blockers. 5
Additional Therapies for Select Patients
Ivabradine
Ivabradine reduces hospitalization risk in adult patients with stable, symptomatic chronic HFrEF. 8, 4 It can be used in selected patients, particularly those with heart rate >70 bpm despite beta-blocker therapy. 5
Device Therapy
Cardiac resynchronization therapy (CRT) is recommended for patients in sinus rhythm with LVEF ≤35%, QRS duration ≥150 ms, and left bundle branch block morphology who remain symptomatic. 2 Implantable cardioverter-defibrillators (ICD) are considered for primary prevention in patients with LVEF ≤35% and ischemic heart disease. 2
When to Refer for Advanced Heart Failure Care
Refer patients to a heart failure specialty team if they experience:
- Persistent low blood pressure with major symptoms despite optimization attempts 2
- Inability to uptitrate GDMT due to hemodynamic intolerance 2
- Refractory symptoms on optimal medical therapy 2
- Fulfillment of 2018 HFA-ESC criteria for advanced HF 9
Advanced HF teams can assess suitability for advanced therapies including mechanical circulatory support, transplantation, and palliative care aligned with patient goals. 1