What are the treatment guidelines for heart failure with reduced ejection fraction (HFrEF)?

Treatment Guidelines for Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should be initiated on four foundational medication classes as soon as possible after diagnosis: an angiotensin receptor-neprilysin inhibitor (ARNI) or ACE inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor—this quadruple therapy reduces cardiovascular death and hospitalization. 1

Core Pharmacological Therapy

First-Line Quadruple Therapy

The modern standard for HFrEF management consists of four drug classes initiated simultaneously or in rapid sequence:

1. Renin-Angiotensin System Inhibition:

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors as it provides superior mortality reduction (at least 20% risk reduction) and should replace ACE inhibitors in symptomatic patients 2, 1
• If switching from an ACE inhibitor, a mandatory 36-hour washout period is required to prevent angioedema 3, 4
• Start sacubitril/valsartan at 49/51 mg twice daily and titrate to target dose of 97/103 mg twice daily every 2-4 weeks as tolerated 3, 4
• For severe renal impairment, start at the lowest dose (24/26 mg twice daily) 3
• If ARNI is not tolerated or available, use an ACE inhibitor or ARB 2, 1

2. Beta-Blockers:

• Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol—these specific agents reduce mortality by at least 20% and decrease sudden cardiac death 2
• Initiate at low doses in clinically stable patients and gradually up-titrate to maximum tolerated doses 2, 1
• Continue beta-blockers even when initiating ARNI therapy 3

3. Mineralocorticoid Receptor Antagonists (MRAs):

• Spironolactone or eplerenone are indicated for all symptomatic patients with LVEF ≤35% to reduce mortality and hospitalization 2, 1
• These agents provide at least 20% mortality reduction and reduce sudden cardiac death 2
• Monitor renal function and serum potassium levels closely due to hyperkalemia risk 1, 5
• Spironolactone is indicated for NYHA Class III-IV heart failure with reduced ejection fraction 5

4. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors:

• SGLT2 inhibitors should be initiated in all HFrEF patients regardless of diabetes status as they significantly reduce cardiovascular and all-cause mortality 1, 6
• This represents the newest addition to foundational therapy and is now considered essential first-line treatment 7, 8

Diuretic Therapy

• Diuretics are recommended to improve symptoms and exercise capacity in patients with signs or symptoms of congestion 2
• Diuretic requirements may decrease after initiating sacubitril/valsartan due to enhanced natriuresis, requiring dose adjustments 3

Device Therapy

Implantable Cardioverter-Defibrillator (ICD)

Primary Prevention:

• ICD is 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 2, 1
• Strongest indication in ischemic cardiomyopathy with mild symptoms 2
• Do not implant within 40 days of myocardial infarction as it does not improve prognosis during this period 2

Secondary Prevention:

• ICD is recommended for patients who have recovered from ventricular arrhythmia causing hemodynamic instability 2

Cardiac Resynchronization Therapy (CRT)

• CRT is 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 2, 1
• CRT is also recommended for QRS duration 130-149 msec with LBBB morphology 2
• CRT is preferred over right ventricular pacing in patients with HFrEF who have an indication for ventricular pacing 2
• Cardiac resynchronization is only recommended for select populations with meaningfully prolonged QRS duration 2

Additional Therapies for Selected Patients

Ivabradine

• Consider in patients who remain symptomatic despite optimal therapy, though survival benefit is modest or negligible in the broad HFrEF population 2, 6

Hydralazine/Isosorbide Dinitrate

• Can prolong survival but may be inferior to ACE inhibitors for mortality 2
• Has a role in certain patients, particularly those intolerant to other agents 6

Vericiguat

• Reduces heart failure hospitalization in high-risk patients with HFrEF 6

Critical Implementation Strategies

Titration Approach

• Use a forced-titration strategy: initiate at low doses and systematically increase every 2-4 weeks to achieve target doses 2, 3, 4
• Target doses provide maximum mortality benefit—do not underdose due to concerns about side effects 3
• If hypotension occurs with ARNI, consider temporary dose reduction rather than discontinuation, as 40% of patients can be restored to target doses 3

Monitoring Requirements

• Check renal function and electrolytes within 1-2 weeks after initiating ARNI and with each dose increase 3
• Monitor blood pressure closely during initiation and titration 3
• Regular monitoring of potassium and renal function is essential with MRA therapy 1, 5

Medications to Avoid

• Diltiazem or verapamil are contraindicated in HFrEF as they increase risk of worsening heart failure and hospitalization 2
• Do not combine ARB with both ACE inhibitor and MRA due to increased risk of renal dysfunction and hyperkalemia 2
• Never co-administer ARNI with ACE inhibitors—strict 36-hour washout required 3, 4

Advanced Heart Failure Management

• Refer patients with advanced HF who wish to prolong survival to a specialized heart failure team 1
• Consider mechanical circulatory support for eligible patients with persistent advanced symptoms 1
• Timely referral to HF specialists is necessary for patients with persistent advanced symptoms or worsening HF despite optimal therapy 8