Initial Management of Heart Failure with Reduced Ejection Fraction (HFrEF)
Start all four core medication classes simultaneously at low doses with gradual titration, beginning with SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) first, followed by beta-blockers (if heart rate >70 bpm) and ARNi/ACE inhibitors. 1, 2
Core Four-Pillar Medication Strategy
First-Line Initiation (Start These First)
SGLT2 Inhibitors (dapagliflozin or empagliflozin) should be initiated immediately as they provide rapid benefits with minimal blood pressure effects and remain effective even with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin). 1, 2 These agents reduce the risk of HF hospitalization and cardiovascular death. 3
Mineralocorticoid Receptor Antagonists (spironolactone or eplerenone) should be started early for patients with LVEF ≤35% and NYHA class II-IV symptoms, as they have minimal effect on blood pressure but provide significant mortality benefit. 1, 2 Monitor serum creatinine (should be ≤2.5 mg/dL in men and ≤2.0 mg/dL in women) and potassium (should be <5.0 mEq/L). 4
Second-Line Initiation (Add After First Two)
Beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) should be initiated at low doses if heart rate >70 bpm. 3 Selective β₁ receptor blockers may be preferred due to lesser blood pressure-lowering effects compared to non-selective beta-blockers. 3 These agents reduce mortality by at least 20% and decrease sudden death risk. 3
ARNi (sacubitril/valsartan) is recommended for NYHA class II-III symptoms, starting with low dose (24/26 mg to 49/51 mg twice daily for adults). 1, 5 This should replace ACE inhibitors or ARBs after a 36-hour washout period. 5 If ARNi is not feasible due to cost or tolerability, use ACE inhibitors as an alternative (or ARBs if ACE inhibitors cause cough or angioedema). 2, 4
Titration Strategy
Titrate medications every 2-4 weeks as tolerated, increasing one drug at a time using small increments until the highest tolerated or target dose is achieved. 3, 1 The target maintenance dose for sacubitril/valsartan is 97/103 mg twice daily. 5 This sequential approach allows identification of which medication causes adverse effects if they occur. 2
Special Considerations for Low Blood Pressure
For patients with systolic blood pressure <100 mmHg, start with SGLT2 inhibitors and MRAs first since they have minimal BP-lowering effects. 3, 2 Consider starting sacubitril/valsartan at very low doses (25 mg twice daily) or using low-dose ACE inhibitors initially. 3 If beta-blockers are not tolerated hemodynamically and the patient is in sinus rhythm, ivabradine may be used as an alternative to facilitate beta-blocker titration later. 3, 2
Diuretic Management
Loop diuretics should be prescribed for patients with signs or symptoms of fluid retention to alleviate congestion. 3 Adjust diuretics according to volume status to avoid overdiuresis, which can lower blood pressure and impair tolerance of other HF medications. 3, 2 Excessive diuresis is a common pitfall that prevents optimal GDMT titration. 2
Monitoring Requirements
During active titration, monitor serum electrolytes, urea nitrogen, creatinine, blood pressure, and heart rate regularly (every 2-4 weeks). 1, 2 Check renal function and potassium closely when using ACE inhibitors/ARBs/ARNi and MRAs. 1, 2
Provide comprehensive discharge instructions including daily weight monitoring, dietary sodium restriction, medication adherence, activity level, and specific instructions on when to seek medical attention for worsening symptoms. 1
Critical Pitfalls to Avoid
Do not use the traditional step-by-step approach that delays comprehensive therapy - simultaneous initiation of all four pillars provides faster symptom relief and mortality benefit. 2 Even lower-than-target doses provide significant benefits, so do not withhold medications due to inability to reach target doses. 2
Do not discontinue GDMT during hospitalizations for HF exacerbations unless there is hemodynamic instability or specific contraindications. 1, 2 Continuation of GDMT during hospitalization is associated with lower risk of post-discharge death and readmission. 2 Even with mild renal function decrease or asymptomatic blood pressure reduction, GDMT should not routinely be discontinued. 2
Avoid nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and calcium channel blockers as they can worsen HF outcomes. 4
Device Therapy Considerations
ICD is recommended for patients with LVEF ≤35%, NYHA class II-III symptoms on optimal medical therapy for ≥3 months, and expected survival >1 year with good functional status. 3 For ischemic cardiomyopathy, wait at least 40 days post-myocardial infarction. 3
Cardiac resynchronization therapy (CRT) is recommended for patients in sinus rhythm with LVEF ≤35%, NYHA class III-IV symptoms despite GDMT, and QRS duration ≥150 ms with left bundle branch block morphology. 3, 4