What is the recommended initial drug regimen for Heart Failure with Reduced Ejection Fraction (HFrEF)?

Recommended Drug Regimen for HFrEF

The recommended initial drug regimen for HFrEF consists of four foundational medication classes that should be initiated rapidly: an ARNI (sacubitril/valsartan) or ACE inhibitor, an evidence-based beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor—all started together as soon as the diagnosis is confirmed, with diuretics added as needed for volume management. 1, 2

Core Four-Pillar Therapy

First-Line Agents (Start All Four Classes)

Renin-Angiotensin System Modulation:

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors as the initial RAS modulator, given its superior mortality and hospitalization reduction (HR 0.80 for CV death or HF hospitalization, HR 0.84 for all-cause mortality, p<0.0001) 3
• Start sacubitril/valsartan at 49/51 mg twice daily, uptitrate every 2-4 weeks to target dose of 97/103 mg twice daily 3
• Critical safety requirement: Allow 36-hour washout period if switching from an ACE inhibitor to avoid angioedema 3
• If ARNI is not tolerated or contraindicated, use an ACE inhibitor; if ACE inhibitor causes cough or angioedema, substitute an ARB (candesartan or valsartan) 4

Beta-Blockers:

• Use only evidence-based agents: carvedilol, metoprolol succinate (sustained-release), or bisoprolol 4, 1
• Initiate concurrently with RAS inhibition, not sequentially 1
• 92% of patients in contemporary practice receive beta-blockers within 3 months of diagnosis 2

Mineralocorticoid Receptor Antagonists (MRA):

• Add spironolactone or eplerenone in NYHA class II-IV patients 4, 1
• Mandatory monitoring requirements: Serum creatinine ≤2.5 mg/dL (men) or ≤2.0 mg/dL (women), and potassium <5.0 mEq/L before initiation 4
• Despite guideline recommendations, only 35-46% of eligible patients receive MRAs, representing a major treatment gap 2

SGLT2 Inhibitors:

• Now a class I recommendation as foundational therapy, reducing CV and all-cause mortality regardless of diabetes status 5, 1
• Should be initiated early, though real-world data shows only 26-30% receive SGLT2i in the first year after diagnosis 2

Diuretic Therapy

• Loop diuretics are first-line for volume overload and symptom relief, but do not modify disease progression 4, 6
• Titrate to achieve euvolemia, then maintain lowest effective dose 6

Additional Agents for Specific Populations

Hydralazine/Isosorbide Dinitrate:

• Add in self-identified African American patients with NYHA class II-IV HF already on diuretics, ACE inhibitors, and beta-blockers 4
• Also consider in patients intolerant to all RAS inhibitors 4

Ivabradine:

• Use in selected patients with HFrEF, particularly those in sinus rhythm with heart rate ≥70 bpm despite beta-blocker therapy 4, 5

Vericiguat:

• Soluble guanylate cyclase stimulator that reduces HF hospitalization in high-risk patients with recent decompensation 5

Implementation Strategy

Rapid Initiation Approach:

• All four foundational drug classes should be started together within the first 3 months of diagnosis, not sequentially 1, 2
• The PARADIGM-HF trial demonstrated that 94% of patients were on beta-blockers, 58% on MRAs, and 82% on diuretics at baseline, establishing the feasibility of multi-drug regimens 3

Common Pitfall to Avoid:

• Do not delay initiation of one class while uptitrating another—this "start low, go slow" sequential approach is outdated 1
• The evidence shows most benefit when medications from all four classes are used in conjunction 1

Monitoring During Titration:

• Renal function and potassium levels require careful monitoring, especially with MRA use 4
• Blood pressure monitoring is essential but should not prevent appropriate dosing if systolic BP remains ≥100 mmHg 3

Device Therapy Considerations

• Cardiac resynchronization therapy (CRT) for interventricular dyssynchrony 5
• Implantable cardioverter-defibrillators (ICD) for severe LV dysfunction, particularly ischemic etiology 5
• Only 18% receive CRT/ICD >12 months after diagnosis, suggesting underutilization 2