What is the recommended treatment for heart failure with reduced ejection fraction (HFrEF)?

Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should be started on quadruple therapy as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with diuretics for volume management. 1

Foundational Quadruple Therapy

The four medication classes provide approximately 73% mortality reduction over 2 years when used together and should be initiated simultaneously rather than sequentially. 1

1. SGLT2 Inhibitors (Start First)

• Reduce cardiovascular death and HF hospitalization regardless of diabetes status 1
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months), making them ideal first agents 1
• Should be added if not already prescribed 1

2. Mineralocorticoid Receptor Antagonists (Start First)

• Spironolactone or eplerenone provide at least 20% mortality reduction and reduce sudden cardiac death 1
• Recommended for all symptomatic patients with LVEF ≤35% 1
• Minimal blood pressure effect allowing early initiation 1
• Require monitoring of renal function and serum potassium levels 1
• FDA-approved for NYHA Class III-IV heart failure with reduced ejection fraction to increase survival, manage edema, and reduce hospitalization 2

3. Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

• Sacubitril/valsartan is preferred over ACE inhibitors for symptomatic patients, providing superior mortality reduction of at least 20% 1
• Recommended starting dose for adults is 49 mg/51 mg orally twice daily, with target maintenance dose of 97 mg/103 mg orally twice daily 3
• Adjust doses every 2 to 4 weeks to target maintenance dose as tolerated 3
• Reduce starting dose to half for patients not currently taking an ACE inhibitor/ARB or on low doses, severe renal impairment, or moderate hepatic impairment 3
• Should replace ACE inhibitors in patients remaining symptomatic despite treatment with ACEi/ARBs, beta-blockers, and MRAs 1

4. Beta-Blockers

• Evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) reduce mortality by at least 20% and decrease sudden cardiac death 1
• Recommended for all patients with current or previous symptoms of chronic HFrEF 1
• Should be initiated in clinically stable patients at low dose and gradually up-titrated to maximum tolerated dose 1

Diuretics for Volume Management

• Loop diuretics are essential for congestion control but do not reduce mortality 1
• Starting doses: 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 1

Titration Strategy

Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved, starting with SGLT2 inhibitor and MRA first. 1

For Patients with Low Blood Pressure:

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 1
• Start SGLT2 inhibitor and MRA first, then add beta-blocker or very low-dose ARNI 1
• GDMT medications have proven efficacy and safety across all baseline systolic blood pressure levels, with benefits maintained even in patients with SBP <110 mmHg 1

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• Can prolong survival but may be inferior to ACE inhibitors for mortality 1

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1
• Starting dose: 2.5-5 mg twice daily 1
• Survival benefit is modest or negligible in the broad HFrEF population 1

Device Therapy

Implantable Cardioverter-Defibrillator (ICD)

• Recommended for patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, who are expected to survive >1 year with good functional status 1
• Indicated for primary prevention in ischemic cardiomyopathy with mild symptoms 1
• Indicated for secondary prevention in patients who have recovered from ventricular arrhythmia causing hemodynamic instability 1

Cardiac Resynchronization Therapy (CRT)

• Recommended for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and left bundle branch block (LBBB) morphology with LVEF ≤35% despite optimal medical therapy 1
• Class I indication if QRS ≥130 msec and LBBB in sinus rhythm 1

Critical Contraindications

• Avoid combining ACE inhibitor with ARNI 1, 3
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1
• Avoid combining ARB with both ACE inhibitor and MRA 1
• Avoid concomitant use with aliskiren in patients with diabetes 3
• Avoid diltiazem or verapamil in HFrEF as they increase risk of worsening heart failure and hospitalization 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes 1
• Accepting suboptimal doses 1
• Stopping medications for asymptomatic hypotension 1
• Inadequate monitoring 1
• Using non-evidence-based beta-blockers 1
• Adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms in clinical trials 1

Monitoring Requirements

• Check renal function and serum potassium before starting therapy 1
• Recheck within 1-2 weeks after initiation 1
• Monitor for signs and symptoms of angioedema and hypotension 3
• Patient education about transient dizziness as a side effect of life-prolonging drugs improves compliance 1