What medications should be prescribed for a patient with heart failure with reduced ejection fraction (HFrEF)?

Medications for Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should be started on four foundational medication classes simultaneously within 2-4 weeks of diagnosis: an SGLT2 inhibitor, a beta-blocker, an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), and a mineralocorticoid receptor antagonist (MRA), along with loop diuretics for volume management. 1, 2

The Four Pillars of HFrEF Treatment

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin should be initiated immediately, regardless of diabetes status 1, 2
• These agents reduce cardiovascular death and heart failure hospitalization by approximately 26% with minimal blood pressure effects, making them ideal first agents 2, 3
• No dose titration required—start at target dose of 10 mg daily 3
• Well-tolerated with rapid onset of benefit within weeks 4

2. Beta-Blockers (Start Simultaneously with SGLT2i)

• Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol 2
• These reduce mortality by at least 20% and decrease sudden cardiac death 2
• Starting doses: Carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily 2
• Titrate every 1-2 weeks to target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily 2

3. ARNI (Sacubitril/Valsartan) - Preferred Over ACE Inhibitors

• Sacubitril/valsartan is superior to ACE inhibitors, providing 20% greater mortality reduction 2, 5
• Start 1-2 weeks after initiating SGLT2i and beta-blocker 4
• Starting dose: 24/26 mg or 49/51 mg twice daily (lower dose for patients not on ACE inhibitor/ARB, severe renal impairment, or moderate hepatic impairment) 2
• Target dose: 97/103 mg twice daily 2
• Critical: Must wait 36 hours after stopping ACE inhibitor before starting ARNI to avoid angioedema 2
• If ARNI not tolerated, use ACE inhibitor (lisinopril 20-35 mg daily or perindopril 4-8 mg daily) or ARB 2, 6

4. Mineralocorticoid Receptor Antagonists (MRAs)

• Start 1-2 weeks after ARNI initiation, or can be compressed/reordered based on patient circumstances 4
• Spironolactone or eplerenone for all symptomatic patients with LVEF ≤35% 1, 2
• Provide at least 20% mortality reduction and reduce sudden cardiac death 2
• Starting doses: Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily 2
• Requires monitoring of renal function and serum potassium levels (check within 1-2 weeks of initiation) 2, 6

5. Loop Diuretics (Essential for Volume Management)

• Furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily 2
• Essential for congestion control but do not reduce mortality 2
• Adjust dose based on volume status and symptoms 2

Rapid Sequencing Strategy

Week 1: Start SGLT2 inhibitor (dapagliflozin 10 mg daily) + beta-blocker (low dose) + loop diuretic as needed 2, 4

Week 2-3: Add sacubitril/valsartan (starting dose), continue uptitrating beta-blocker 2, 4

Week 3-4: Add MRA (spironolactone 12.5-25 mg or eplerenone 25 mg daily) 2, 4

Ongoing: Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with NYHA Class III-IV

• Hydralazine/isosorbide dinitrate in addition to foundational therapy 2
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• Target dose: hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 2

For Persistent Tachycardia Despite Maximally Tolerated Beta-Blocker

• Ivabradine if heart rate ≥70 bpm in sinus rhythm 2, 7
• Starting dose: 2.5-5 mg twice daily 2
• Survival benefit is modest or negligible in broad HFrEF population 2

Critical Contraindications and Drug Combinations to Avoid

• Never combine ACE inhibitor with ARNI—risk of severe angioedema 2
• Never use triple combination of ACE inhibitor + ARB + MRA—excessive risk of hyperkalemia and renal dysfunction 2
• Avoid diltiazem or verapamil—they increase risk of worsening heart failure and hospitalization 2
• Avoid routine use of nitrates or phosphodiesterase-5 inhibitors in HFpEF (no benefit) 1

Special Populations and Dose Adjustments

Patients with Low Blood Pressure

• Do not withhold therapy for asymptomatic low blood pressure with adequate perfusion 2
• Start SGLT2 inhibitor and MRA first (minimal BP effect), then add beta-blocker or very low-dose ARNI 2
• Uptitrate cautiously while monitoring symptoms 2

Patients with Renal Impairment

• SGLT2 inhibitors are safe and effective even with eGFR as low as 25 mL/min/1.73 m² 3
• Use lower starting doses of ARNI and monitor renal function closely 2
• MRA requires careful potassium and creatinine monitoring 2, 6

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start within 2-4 weeks, not 6+ months 2, 4
• Accepting suboptimal doses—low doses have substantial benefit, but continue uptitration when tolerated 2, 4
• Stopping medications for asymptomatic hypotension—only stop if symptomatic or inadequate perfusion 2
• Using non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate)—only use carvedilol, metoprolol succinate, or bisoprolol 2
• Inadequate monitoring—check renal function and potassium within 1-2 weeks of starting ARNI or MRA 2, 6
• Sequential rather than simultaneous initiation—foundational drugs act independently and should be started together 4

Device Therapy Considerations

• Implantable cardioverter-defibrillator (ICD) for patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy 2
• Cardiac resynchronization therapy (CRT) for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and left bundle branch block morphology with LVEF ≤35% 2

Patients with Improved LVEF (>40%)

• Continue all HFrEF medications—do not discontinue foundational therapy even if LVEF improves 1