What are the recommended medications for a patient with heart failure with reduced ejection fraction (HFrEF)?

Heart Failure with Reduced Ejection Fraction: Recommended Medications

All patients with HFrEF should immediately start four foundational medication classes simultaneously: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (sacubitril/valsartan preferred over ACE inhibitor/ARB), along with loop diuretics for volume management. 1, 2

The Four Pillars of HFrEF Therapy

1. Renin-Angiotensin System Inhibition (First Choice: ARNI)

Sacubitril/valsartan (ARNI) is the preferred first-line agent over ACE inhibitors or ARBs for patients with NYHA class II-III symptoms, providing at least 20% mortality reduction superior to enalapril. 1, 2, 3

• Starting dose: 49/51 mg twice daily 1, 3
• Target dose: 97/103 mg twice daily 1, 3
• Titration schedule: Double the dose every 2-4 weeks as tolerated 1, 3

Critical washout requirement: If switching from an ACE inhibitor, allow a mandatory 36-hour washout period to prevent angioedema. 1, 3

Alternative options when ARNI is not feasible:

• ACE inhibitors (enalapril, lisinopril, ramipril) reduce morbidity and mortality in patients with previous or current symptoms of chronic HFrEF 1
• ARBs (losartan, valsartan, candesartan) are recommended for patients intolerant to ACE inhibitors due to cough or angioedema 1

2. Beta-Blockers (Evidence-Based Only)

Use only one of the three beta-blockers proven to reduce mortality: bisoprolol, carvedilol, or sustained-release metoprolol succinate. 1, 2

• These agents reduce mortality by at least 20% and decrease sudden cardiac death 2
• Start at low doses in clinically stable patients and gradually up-titrate to maximum tolerated dose 2
• Common pitfall: Using non-evidence-based beta-blockers like atenolol or metoprolol tartrate provides no mortality benefit 2

3. Mineralocorticoid Receptor Antagonists (MRAs)

Spironolactone or eplerenone are recommended for NYHA class II-IV patients with LVEF ≤35% to reduce mortality and hospitalization by at least 20%. 1, 2

Eligibility criteria:

• eGFR >30 mL/min/1.73 m² 1, 2
• Serum potassium <5.0 mEq/L 1

Monitoring requirements: Check potassium and renal function at 1-2 weeks after initiation and closely thereafter to minimize hyperkalemia and renal insufficiency risk. 1, 2

Important safety note: Sacubitril/valsartan actually reduces hyperkalemia risk when combined with MRAs compared to ACE inhibitors plus MRAs, making this combination safer than traditional approaches. 2

4. SGLT2 Inhibitors (Newest Pillar)

Dapagliflozin or empagliflozin reduce cardiovascular death and HF hospitalization regardless of diabetes status. 1, 2

• Empagliflozin: Can be used if eGFR ≥30 mL/min/1.73 m² 2
• Dapagliflozin: Can be used if eGFR ≥20 mL/min/1.73 m² 2
• Key advantage: Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making them ideal first agents 2
• No up-titration required; benefits occur within weeks of initiation 2

Diuretics for Volume Management

Loop diuretics are essential for congestion control but do not reduce mortality. 2

Starting doses:

• Furosemide: 20-40 mg once or twice daily 2
• Torsemide: 10-20 mg once daily 2
• Bumetanide: 0.5-1.0 mg once or twice daily 2

Titration goal: Achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 2

Optimal Initiation Strategy

Start all four medication classes simultaneously as soon as possible after diagnosis. 2

Recommended sequence for up-titration:

1. Start SGLT2 inhibitor and MRA first (minimal BP effects) 2
2. Add beta-blocker if heart rate >70 bpm 2
3. Add low-dose ARNI/ACEi/ARB 2
4. Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2

This quadruple therapy provides approximately 73% mortality reduction over 2 years and 5.3 additional life-years compared to no treatment. 2

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate

Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 1, 2

• Starting dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• Can prolong survival but may be inferior to ACE inhibitors for mortality 2

Ivabradine

Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker. 1, 2

• Starting dose: 2.5-5 mg twice daily 2
• Survival benefit is modest or negligible in the broad HFrEF population 2

Managing Low Blood Pressure During Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion. 2

GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2

For symptomatic hypotension (SBP <80 mmHg or major symptoms):

1. Address reversible non-HF causes first: Stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration/infection 2

2. Non-pharmacological interventions: Compression leg stockings for orthostatic symptoms, exercise and physical training programs, adequate salt and fluid intake if not volume overloaded 2

3. If symptoms persist, reduce GDMT in this specific order:

   • If heart rate >70 bpm: Reduce ACEi/ARB/ARNI dose first 2
   • If heart rate <60 bpm: Reduce beta-blocker dose first 2
   • Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 2

Critical warning: Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 2

Medications to Avoid

Contraindicated combinations:

• ACE inhibitor with ARNI (risk of angioedema) 1, 2
• Triple combination of ACE inhibitor + ARB + MRA (hyperkalemia and renal dysfunction) 1, 2

Harmful agents in HFrEF:

• Diltiazem or verapamil increase risk of worsening heart failure and hospitalization 2
• Non-evidence-based beta-blockers (atenolol, metoprolol tartrate) provide no mortality benefit 2

Monitoring Requirements

Check at 1-2 weeks after each dose increment:

• Blood pressure 2
• Renal function (modest increases in creatinine up to 30% above baseline are acceptable and should not prompt discontinuation) 2
• Electrolytes (potassium requires close monitoring with MRAs) 2

More frequent monitoring required in: Elderly patients and those with chronic kidney disease 2

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes - start simultaneously 2
2. Accepting suboptimal doses - aggressively up-titrate to target doses 2
3. Stopping medications for asymptomatic hypotension - adverse events occur in 75-85% of HFrEF patients regardless of treatment 2
4. Inadequate monitoring - check labs 1-2 weeks after each dose change 2
5. Using non-evidence-based beta-blockers - only bisoprolol, carvedilol, or metoprolol succinate 1, 2