What is the current optimal therapy for Heart Failure with Reduced Ejection Fraction (HFrEF)?

Optimal Therapy for HFrEF

The current optimal therapy for HFrEF consists of four foundational drug classes initiated simultaneously or in rapid sequence: an SGLT2 inhibitor (dapagliflozin 10mg daily or empagliflozin 10mg daily), an ARNI (sacubitril/valsartan 97/103mg twice daily as target dose), a beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), and a mineralocorticoid receptor antagonist (spironolactone or eplerenone), all titrated to target or maximally tolerated doses. 1, 2

Core Four-Drug Regimen

SGLT2 Inhibitors (First Priority)

• Start dapagliflozin 10mg daily or empagliflozin 10mg daily immediately at full dose—no titration required. 1, 2
• SGLT2 inhibitors demonstrate consistent mortality and hospitalization reduction with high certainty evidence, are well-tolerated, and provide rapid symptom improvement. 1
• These agents work through mechanisms independent of neurohormonal blockade, making them complementary to all other HFrEF therapies. 1
• Ensure eGFR >25 mL/min/1.73m² before initiation. 2

ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Replace ACE inhibitors or ARBs with sacubitril/valsartan, starting at 49/51mg twice daily and titrating to target dose of 97/103mg twice daily after 2-4 weeks. 1, 2
• If blood pressure <100 mmHg, start at 24/26mg twice daily. 1, 2
• Mandatory 36-hour washout period when switching from ACE inhibitors to avoid angioedema. 1, 3
• ARNIs improve quality of life with high certainty evidence and reduce mortality compared to ACE inhibitors. 1
• For patients naive to ACE inhibitors/ARBs, ARNI can be initiated de novo. 1

Beta-Blockers

• Start one of three evidence-based beta-blockers: carvedilol 3.125mg twice daily, metoprolol succinate 12.5-25mg daily, or bisoprolol 1.25mg daily. 1, 2
• Target doses: carvedilol 25mg twice daily (<85kg) or 50mg twice daily (≥85kg); metoprolol succinate 200mg daily; bisoprolol 10mg daily. 1
• Titrate every 2-4 weeks as tolerated, monitoring heart rate and blood pressure. 2

Mineralocorticoid Receptor Antagonists (MRAs)

• Start spironolactone 12.5-25mg daily or eplerenone 25mg daily, targeting 25-50mg daily for spironolactone or 50mg daily for eplerenone. 1, 2
• Monitor potassium and renal function at 2-3 days, then monthly for 3 months. 2
• Indicated when LVEF <35% or persistent NYHA Class II-IV symptoms. 1

Additional Therapies Based on Clinical Phenotype

Loop Diuretics

• Use for symptomatic congestion at the lowest effective dose to achieve euvolemia. 1
• Loop diuretics lack mortality benefit but are essential for symptom control. 1
• Titrate based on daily weights and clinical signs of congestion. 2

Ivabradine

• Add ivabradine 5mg twice daily (target 7.5mg twice daily) if heart rate remains ≥70 bpm despite maximally tolerated beta-blocker, in patients with sinus rhythm and LVEF ≤35%. 1
• Ivabradine improves quality of life with high certainty evidence. 1

Hydralazine-Isosorbide Dinitrate

• Consider in self-identified Black patients with NYHA Class III-IV symptoms despite optimal GDMT. 1
• Also consider in patients intolerant to ACE inhibitors, ARBs, and ARNI. 1
• Improves quality of life with high certainty evidence. 1

Intravenous Iron

• Administer IV iron (ferric carboxymaltose) in patients with iron deficiency (ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20%) to improve symptoms and quality of life. 1
• High certainty evidence for quality of life improvement. 1

Vericiguat

• Consider vericiguat 10mg daily in patients with worsening HF (recent hospitalization or need for IV diuretics) despite optimal GDMT, particularly with elevated natriuretic peptides. 1
• Less effective in patients with very recent hospitalization or very high natriuretic peptides. 1

Implementation Strategy

Sequencing and Timing

• Initiate SGLT2 inhibitor immediately at full dose—this is the easiest and safest medication to start. 1, 2
• Begin all four foundational drug classes within the first few weeks of diagnosis, not sequentially over months. 1
• Uptitrate one medication at a time in small increments every 2-4 weeks. 2
• Close follow-up within 1-2 weeks of medication changes to monitor blood pressure, heart rate, renal function, and electrolytes. 2

Common Pitfalls to Avoid

• Do not delay SGLT2 inhibitor initiation—these agents are safe, well-tolerated, and provide early benefit. 1
• Do not accept suboptimal doses of beta-blockers and ARNI—titrate to target doses or document intolerance. 1
• Do not continue ACE inhibitors when ARNI is available and tolerated—ARNI provides superior outcomes. 1
• Do not use digoxin for mortality benefit—its role is limited to rate control in atrial fibrillation with low blood pressure. 1
• Do not routinely anticoagulate based solely on low LVEF—this practice is no longer recommended. 4

Monitoring Parameters

• Assess blood pressure, heart rate, renal function (creatinine, eGFR), and electrolytes (potassium) at baseline and with each medication change. 2
• Monitor daily weights and symptoms of congestion. 2
• Reassess functional capacity and quality of life at each visit. 2

Quality of Life Considerations

When discussing treatment goals with patients, emphasize that ARBs, ARNIs, SGLT2 inhibitors, ivabradine, hydralazine-nitrate, and IV iron all improve quality of life with high certainty evidence, while effects of ACE inhibitors, beta-blockers, and oral iron on quality of life remain inconclusive despite mortality benefits. 1