What is the management of heart failure according to stages of heart failure and Left Ventricular Ejection Fraction (LVEF) in a broad patient population across various age groups and with different comorbid conditions?

Management of Heart Failure by Stage and LVEF

Heart failure management follows a stage-based approach (A through D) with treatment intensity escalating as disease progresses, while LVEF classification (≤40%, 41-49%, ≥50%) determines specific pharmacologic strategies, with the 2022 ACC/AHA/HFSA guidelines providing the most current framework for evidence-based therapy. 1

Heart Failure Staging System

The ACC/AHA staging system is unidirectional—patients advance through stages but cannot regress, even if symptoms resolve with treatment 2, 3. A patient who becomes asymptomatic with therapy remains in their current stage and requires continued stage-appropriate treatment 3.

Stage A: At Risk for Heart Failure

Patients have risk factors (hypertension, diabetes, coronary disease, obesity, metabolic syndrome, cardiotoxic drug exposure, family history of cardiomyopathy) but no structural heart disease or symptoms 1, 2.

Management priorities:

• Aggressive blood pressure control to <130/80 mmHg using any antihypertensive agent, with diuretics superior for preventing progression 2
• Statin therapy for patients with atherosclerotic disease to reduce heart failure risk 2
• Diabetes control with A1C monitoring, as dysglycemia directly predicts incident heart failure 2
• Tobacco cessation through strong counseling interventions 2
• Weight management for obesity 2
• ACE inhibitors or ARBs in select patients with hypertension, diabetes, or atherosclerotic disease to prevent structural heart disease development 2

Stage B: Structural Heart Disease Without Symptoms

Patients have crossed a critical threshold with objective structural abnormalities (LV hypertrophy, impaired LV function, prior MI, LVEF ≤40%) but remain asymptomatic 1, 2, 3.

Management priorities for LVEF ≤40%:

• ACE inhibitors are the cornerstone (Class I, Level A) for all patients to prevent symptomatic heart failure and reduce mortality 2, 3, 4
• ARBs as alternative for ACE inhibitor-intolerant patients, particularly post-MI 2
• Evidence-based beta-blockers (Class I, Level B-R) for all patients to prevent symptomatic heart failure 2, 3
• Statins for patients with recent or remote MI/acute coronary syndrome (Class I, Level A) 2
• ICD placement for patients ≥40 days post-MI with LVEF ≤30% for primary prevention of sudden cardiac death 3

Critical contraindications:

• Thiazolidinediones are contraindicated in LVEF <50% due to increased heart failure risk 2
• Nondihydropyridine calcium channel blockers should be avoided in LVEF <50% due to negative inotropic effects 2

Stage C: Symptomatic Heart Failure

Patients have structural heart disease with current or previous symptoms of heart failure 1. Management is stratified by LVEF classification.

LVEF-Based Classification and Treatment

HFrEF (LVEF ≤40%)

Foundational "Fantastic Four" therapy that ALL patients should receive unless contraindicated 5, 6, 7:

1. Renin-angiotensin system inhibition:

   • Angiotensin receptor-neprilysin inhibitor (ARNI/sacubitril-valsartan) preferred over ACE inhibitors or ARBs 5, 6, 7
   • ACE inhibitors or ARBs if ARNI not tolerated 1

2. Beta-blockers (evidence-based agents: carvedilol, metoprolol succinate, bisoprolol) 1, 5, 6

3. Mineralocorticoid receptor antagonists (MRAs) for NYHA class II-IV with LVEF ≤35% 1, 2, 8

   • Spironolactone reduced mortality by 30% in landmark RALES trial 8
   • Exclude if baseline creatinine >2.5 mg/dL or potassium >5.0 mEq/L 8

4. SGLT2 inhibitors significantly reduce cardiovascular and all-cause mortality irrespective of diabetes status 5, 7

Additional therapies:

• Loop diuretics for all patients with fluid retention or history of volume overload 1, 2
• Hydralazine-isosorbide dinitrate particularly beneficial in African American patients or those intolerant to ACE inhibitors/ARBs 2
• Ivabradine for select patients with sinus rhythm and heart rate ≥70 bpm despite beta-blocker therapy 5
• Vericiguat (soluble guanylate cyclase stimulator) reduces heart failure hospitalization in high-risk patients 5
• Digoxin may be added for symptom management and reducing hospitalizations, though it does not reduce mortality 2

Device therapies:

• Cardiac resynchronization therapy (CRT) in patients with interventricular dyssynchrony 1, 5
• Implantable cardioverter-defibrillators (ICDs) in patients with LVEF ≤35% for primary prevention 1, 5
• Transcatheter mitral valve repair in patients with severe secondary mitral regurgitation 5

Diagnostic evaluation:

• Laboratory assessment: CBC, urinalysis, electrolytes, BUN, creatinine, fasting glucose, HbA1c, lipid profile, LFTs, TSH 2
• 12-lead ECG and chest X-ray (PA and lateral) in all patients 2
• 2D echocardiography with Doppler to assess LVEF, LV size, wall thickness, valve function 2
• BNP or NT-proBNP for diagnostic uncertainty, prognosis, and therapy optimization 2
• Coronary angiography (Class IIa) for patients with chest pain, known/suspected CAD without angina (unless ineligible for revascularization), or newly diagnosed heart failure without prior coronary evaluation 2, 9

Critical pitfall: Do not assume non-ischemic cardiomyopathy based solely on negative troponins—up to 70% of HFrEF cases have ischemic etiology, and revascularization can improve outcomes 9. LVEF measured at a single time point has major limitations as 45% of patients with initial LVEF ≤35% improve to >35% over time, and 41% of patients are reclassified before sudden cardiac death events 10.

HFmrEF (LVEF 41-49%)

Patients with mildly reduced ejection fraction are typically in dynamic trajectory—either improving from HFrEF or deteriorating toward HFrEF 1. One LVEF measurement at one time point is inadequate; evaluate trajectory over time and underlying cause 1.

Management approach:

• SGLT2 inhibitors as first-line disease-modifying therapy 7
• Diuretics for symptom management 7
• Consider foundational HFrEF therapies (ACE inhibitors/ARBs, beta-blockers, MRAs) based on individual patient characteristics and trajectory 7

HFpEF (LVEF ≥50%)

Patients with preserved ejection fraction represent at least 50% of heart failure population, with increasing prevalence 1, 11. Diagnosis requires classic signs/symptoms plus additional objective measures of cardiac dysfunction for improved specificity 1.

Diagnostic thresholds for structural abnormalities and elevated filling pressures 1:

• Left atrial volume index >29 mL/m²
• LV mass index >116/95 g/m² (male/female)
• Average E/e' ≥15 for increased filling pressures
• Septal e' <7 cm/s or lateral e' <10 cm/s
• BNP ≥35 pg/mL or NT-proBNP ≥125 pg/mL

Management priorities (Class I recommendations):

• Control systolic and diastolic hypertension according to published guidelines (Level of Evidence: A) 1
• Control ventricular rate in patients with atrial fibrillation (Level of Evidence: C) 1
• Diuretics to control pulmonary congestion and peripheral edema (Level of Evidence: C) 1, 7
• SGLT2 inhibitors as first-line disease-modifying therapy 7

Class IIa recommendations:

• Coronary revascularization reasonable when symptomatic/demonstrable myocardial ischemia adversely affects cardiac function (Level of Evidence: C) 1

Class IIb recommendations:

• Restoration and maintenance of sinus rhythm in atrial fibrillation might improve symptoms (Level of Evidence: C) 1
• Beta-blockers, ACE inhibitors, ARBs, or calcium antagonists in controlled hypertension might minimize symptoms (Level of Evidence: C) 1
• Digitalis usefulness not well established (Level of Evidence: C) 1

Critical context: To date, no drug or drug group has consistently improved survival in HFpEF 11. Preventative measures and effective treatment of underlying causes (hypertension accounts for most US cases) are particularly important 11.

Stage D: Advanced/Refractory Heart Failure

Patients have marked symptoms interfering with daily life and recurrent hospitalizations despite optimal GDMT 1.

Management options:

• Continuous intravenous inotropic support for symptom relief in hospitalized patients, though intermittent infusions should NOT be used for long-term outpatient treatment due to increased mortality risk 1, 2
• Mechanical circulatory support (MCS) devices (LVAD, BiVAD) as bridge to transplant or destination therapy (Class IIa, Level B) 1, 2
• Cardiac transplantation evaluation for eligible candidates (Class I, Level C) 1, 2
• Palliative care/hospice for patients not candidates for advanced therapies 2

MCS referral criteria: LVEF <25%, NYHA class III-IV despite GDMT/CRT, high predicted 1-2 year mortality (markedly reduced peak oxygen consumption, clinical prognostic scores), or dependence on continuous parenteral inotropic support 1. Selection requires multidisciplinary team including advanced HF/transplant cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians 1.

Non-Pharmacologic Management Across All Stages

• Sodium restriction to 2-3 grams daily 2
• Exercise training in stable patients to improve functional capacity 2
• Screening and treatment of sleep disorders including sleep apnea 2
• Management of comorbidities: diabetes, ischemic heart disease, atrial fibrillation crucial through each stage 7