What is the management approach for patients with reduced ejection fraction (EF), specifically those with heart failure with reduced ejection fraction (HFrEF)?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should receive four foundational medication classes initiated simultaneously at low doses and rapidly up-titrated to target doses within 2 months: an ARNI (or ACEi/ARB if ARNI not feasible), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor. 1, 2

Core Pharmacological Therapy (Quadruple Therapy)

First-Line Medications - Start All Four Classes Together

ARNI (Angiotensin Receptor-Neprilysin Inhibitor):

• Sacubitril/valsartan is the preferred first-line renin-angiotensin system inhibitor for patients with NYHA class II-III symptoms to reduce morbidity and mortality 1
• If patients are already on an ACEi or ARB and tolerating it, replace with ARNI rather than continuing the ACEi/ARB 1
• ACEi should only be used when ARNI is not feasible, as it provides inferior mortality benefit compared to ARNI 1
• ARBs are reserved for patients intolerant to both ARNI and ACEi (typically due to cough or angioedema) 1

Beta-Blockers:

• Use only evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• These reduce morbidity and mortality in conjunction with renin-angiotensin system inhibition 1
• For metoprolol succinate in heart failure: start 12.5-25 mg once daily, double dose every 2 weeks to target of 200 mg daily 3
• For carvedilol: indicated for left ventricular dysfunction following myocardial infarction with LVEF ≤40% 4

Mineralocorticoid Receptor Antagonists (MRAs):

• Spironolactone or eplerenone should be initiated early as they typically don't significantly reduce blood pressure 1, 2
• These medications are part of the foundational four-drug regimen proven to reduce mortality 1, 2

SGLT2 Inhibitors:

• Dapagliflozin or empagliflozin are Class 1 recommendations for all HFrEF patients regardless of diabetes status 1, 2
• These should be initiated early as they do not lower blood pressure significantly and can be used safely even in patients with lower baseline blood pressure 1, 2
• Benefits include once-daily dosing, minimal blood pressure effects, and early onset of clinical benefits 2

Implementation Strategy

Rapid Initiation Protocol

Start all four medication classes simultaneously at initial low doses rather than sequentially achieving target doses of fewer medications. 1, 2

• Do not wait to achieve target dose of one medication before starting the next 2
• Increase doses every 1-2 weeks as tolerated, targeting evidence-based doses 2
• The goal is achieving optimal treatment within 2 months of diagnosis 2
• This approach has emerged from recent trials showing early benefit from prompt initiation and large benefits of comprehensive HF therapies over time 1

Managing Low Blood Pressure During Optimization

Low blood pressure alone (even systolic BP <90 mmHg) without symptoms or hypoperfusion is NOT a contraindication to guideline-directed medical therapy. 1, 2

• Patients should continue all four GDMT classes unless hemodynamic instability or cardiogenic shock is present 1, 2
• For systolic BP <80 mmHg or symptomatic hypotension, evaluate for reversible non-HF causes of hypotension first 1, 5
• Consider temporary reduction or discontinuation of non-HF medications that may contribute to hypotension (not HF medications) 1, 5
• SGLT2 inhibitors and MRAs can be safely continued even with lower blood pressure 1
• Beta-blockers, ACEIs/ARBs, or ARNIs should be initiated at low doses and carefully titrated based on blood pressure tolerance 1

Secondary Therapies for Persistent Symptoms

Additional Medications for Select Patients

Hydralazine-Isosorbide Dinitrate:

• Consider for self-identified Black patients with NYHA class III-IV symptoms already on optimal GDMT to reduce morbidity and mortality 1
• Also consider for patients who cannot tolerate ACEi, ARB, or ARNI due to renal insufficiency, hyperkalemia, or hypotension 1

Ivabradine:

• Consider for patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker dose, with LVEF ≤35% and NYHA class II-III symptoms 1

Vericiguat:

• May be considered for patients with worsening HF despite optimal GDMT who have had recent hospitalization or need for IV diuretics 1

Digoxin:

• May reduce hospitalizations in patients with persistent symptoms despite optimal GDMT, particularly those in atrial fibrillation 1

Acute Decompensated HFrEF Management

Start IV loop diuretics immediately in the emergency department without delay, with an initial IV dose equal to or exceeding the chronic oral daily dose. 2

• The initial goal is to stabilize hemodynamic status and treat pulmonary edema 6
• Continue GDMT during hospitalization unless cardiogenic shock or severe hypotension is present 1
• Vasodilators may be used in conjunction with diuretics for pulmonary edema 6

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Indicated for primary prevention if LVEF ≤35% despite ≥3 months of optimal GDMT and life expectancy >1 year 1, 2

Cardiac Resynchronization Therapy (CRT):

• Indicated for patients with LVEF ≤35%, NYHA class II-IV symptoms, sinus rhythm, and left bundle branch block with QRS ≥150 ms 1, 2
• CRT can improve cardiac output and blood pressure by approximately 5% 5

Transcatheter Valve Interventions:

• Consider transcatheter aortic valve replacement (TAVR) for significant aortic stenosis contributing to reduced cardiac output, which can increase systolic blood pressure by an average of 15 mmHg 5
• Consider transcatheter edge-to-edge repair (TEER) for severe mitral regurgitation to improve forward flow and enhance tissue perfusion 5

Advanced Heart Failure Referral

Refer to HF specialty team if patients have any of the following: 2

• Persistent NYHA class III-IV symptoms despite optimal GDMT
• Recurrent hospitalizations for HF
• Need for continuous or intermittent inotropic support
• Consideration for advanced therapies (transplant, mechanical circulatory support)

Common Pitfalls and Caveats

Adverse Events Are Often Misattributed to GDMT:

• In clinical trials, 75-85% of participants reported at least one adverse event, but rates were similar between active medication and placebo arms 1
• Many adverse events reflect the high-risk nature of the HF disease state rather than being attributable to specific therapy 1
• Symptoms occurring while on GDMT should not automatically result in medication discontinuation without careful evaluation 1

Clinical Inertia Remains a Major Barrier:

• Real-world evidence shows poor implementation of GDMT in terms of limited initiation, up-titration, and long-term maintenance 1
• Low blood pressure is among the most common perceived barriers, with 66% of clinicians identifying hypotension as a major concern, though this should rarely prevent GDMT use 1
• Optimal use of ARNI alone would prevent 28,000 deaths annually in the United States, with an additional 34,000 deaths prevented with SGLT2 inhibitor use 1