Medication Recommendations for LVEF of 35%
For a patient with LVEF of 35% (HFrEF), initiate quadruple therapy simultaneously: start an ARNI (sacubitril/valsartan), beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor at low doses, then uptitrate every 2-4 weeks to target doses. 1, 2
Core Medication Regimen (Four Pillars of GDMT)
1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - First Choice
- Sacubitril/valsartan is superior to ACE inhibitors/ARBs and should be the preferred renin-angiotensin system blocker 1, 3, 4
- Starting dose: 49/51 mg twice daily for most patients; use 24/26 mg twice daily if severe renal impairment (eGFR <30), moderate hepatic impairment, age ≥75 years, or systolic BP <100 mmHg 3, 4
- Target dose: 97/103 mg twice daily 3, 4
- Titration: Double the dose every 2-4 weeks as tolerated 1, 3
- Critical washout: If switching from ACE inhibitor, wait 36 hours; no washout needed from ARB 3, 4
2. Beta-Blocker
- Use evidence-based beta-blockers: bisoprolol, carvedilol, or metoprolol succinate (sustained-release) 1, 2
- Start at low doses and uptitrate to target doses proven in clinical trials 1
- Indicated for all patients with current or prior HFrEF symptoms unless contraindicated 1, 2
3. Mineralocorticoid Receptor Antagonist (MRA)
- Add spironolactone or eplerenone for NYHA class II-IV symptoms with LVEF ≤35% 1
- Prerequisites: Creatinine ≤2.5 mg/dL (men) or ≤2.0 mg/dL (women), OR eGFR >30 mL/min/1.73 m², AND potassium <5.0 mEq/L 1
- Monitoring: Check potassium and renal function closely at initiation and regularly thereafter 1, 2
4. SGLT2 Inhibitor
- Dapagliflozin or empagliflozin reduces HF hospitalization and cardiovascular mortality 1, 2
- Class I recommendation regardless of diabetes status 1
- Can be initiated immediately, even during hospitalization 5
Alternative to ARNI (If ARNI Not Tolerated or Available)
If sacubitril/valsartan cannot be used:
- ACE inhibitor (first choice): Start low, titrate to target doses from clinical trials 1
- ARB (if ACE inhibitor intolerant due to cough or angioedema): Start low, titrate to target doses 1
Additional Therapies
Diuretics
- Loop diuretics (furosemide, bumetanide, torsemide) for volume control and congestion 1, 2
- Dose adjusted based on symptoms and volume status 1
Hydralazine-Isosorbide Dinitrate
- For African American patients with NYHA class III-IV symptoms despite optimal GDMT 1
- Can be added to standard therapy 1
Ivabradine
- For persistent symptoms with sinus rhythm, LVEF ≤35%, and heart rate ≥70 bpm despite maximally tolerated beta-blocker 1
Implementation Strategy
Start medications simultaneously, not sequentially - all four pillars can be initiated at low doses at the same time without waiting to reach target dose of one before starting another 2, 3
Uptitration schedule:
- Increase doses every 2-4 weeks as tolerated 1, 3
- Target is to reach evidence-based doses from clinical trials, not just "some dose" 1, 2
- Monitor BP, renal function, electrolytes, and heart rate at each titration 2, 5
Device Therapy Consideration
After ≥3 months of optimal medical therapy, reassess for:
- ICD: If LVEF remains ≤35% with NYHA class II-III symptoms, or LVEF ≤30% with NYHA class II 1, 5
- CRT: If NYHA class II-IV, LVEF ≤35%, LBBB with QRS ≥150 ms 1, 5
Critical Pitfalls to Avoid
- Do not undertitrate - medium doses do not provide the same mortality benefit as target doses 3
- Do not permanently reduce doses for asymptomatic hypotension or mild lab changes; temporary reduction with re-titration is preferred 3
- Do not avoid MRA due to fear of hyperkalemia if creatinine and potassium are within acceptable ranges 1
- Do not use triple combination of ACE inhibitor + ARB + MRA simultaneously - this is potentially harmful 1
- Do not delay SGLT2 inhibitor initiation - it can be started immediately alongside other therapies 1, 5
- Avoid NSAIDs - they worsen renal function and counteract GDMT benefits 2