What are the current guideline‑directed medical therapy recommendations for adults with chronic heart failure, including classification by ejection fraction and recommended drug classes?

Current Guidelines for Chronic Heart Failure Management

All adults with chronic heart failure should be classified by ejection fraction—HFrEF (≤40%), HFmrEF (41-49%), or HFpEF (≥50%)—because treatment strategies differ fundamentally across these categories, with HFrEF having the strongest evidence base for mortality-reducing therapies. 1

Heart Failure Classification by Ejection Fraction

HFrEF (Heart Failure with Reduced Ejection Fraction)

• LVEF ≤40% is the threshold that defines HFrEF and triggers eligibility for all four foundational medication classes with proven mortality benefit. 1, 2
• Transthoracic echocardiography (TTE) is the recommended imaging modality to assess myocardial structure, function, and LVEF for diagnosis and treatment planning. 1

HFmrEF (Heart Failure with Mildly Reduced Ejection Fraction)

• LVEF 41-49% defines this intermediate category, which shares characteristics with both HFrEF and HFpEF. 1, 3
• Evidence for specific therapies in HFmrEF is emerging but remains less robust than for HFrEF. 1, 3

HFpEF (Heart Failure with Preserved Ejection Fraction)

• LVEF ≥50% with objective evidence of cardiac structural/functional abnormalities consistent with LV diastolic dysfunction or raised filling pressures, including elevated natriuretic peptides. 1
• Treatment focuses primarily on symptom management and comorbidity control, with limited mortality-reducing pharmacotherapy options. 1, 4

Guideline-Directed Medical Therapy for HFrEF

The Four Foundational Drug Classes (Quadruple Therapy)

Start all four medication classes simultaneously as soon as possible after HFrEF diagnosis to maximize survival benefit—this approach provides approximately 61% reduction in all-cause mortality (HR 0.39,95% CI 0.32-0.49) and adds 5.3 life-years compared to no treatment. 2

1. SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily reduce cardiovascular death and HF hospitalization regardless of diabetes status. 2
• No dose titration required; benefits occur within weeks of initiation. 2
• Can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin or ≥20 mL/min/1.73 m² for dapagliflozin. 2
• Minimal blood pressure effect makes them ideal first agents, especially in patients with borderline BP. 2

2. Renin-Angiotensin System Inhibitors

Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors for symptomatic patients (NYHA class II-IV) because it provides superior mortality reduction of at least 20% compared to enalapril. 1, 2, 5

• Starting dose: 24/26 mg (referred to as 50 mg) twice daily, or 49/51 mg (100 mg) twice daily if previously on adequate ACE-I/ARB doses. 1, 5
• Target dose: 97/103 mg (200 mg) twice daily. 1, 5
• Requires systolic BP >100 mmHg, eGFR >30 mL/min/1.73 m², and potassium <5.2 mmol/L before initiation. 5
• Do not combine with ACE inhibitors due to angioedema risk. 1, 2

If ARNI not tolerated or contraindicated: Use ACE inhibitor (e.g., enalapril, lisinopril, ramipril) or ARB (e.g., losartan, valsartan, candesartan). 1, 2

3. Evidence-Based Beta-Blockers

• Only three beta-blockers have proven mortality benefit: carvedilol, metoprolol succinate (extended-release), or bisoprolol—these reduce mortality by at least 20% and decrease sudden cardiac death. 1, 2
• Do not use metoprolol tartrate (immediate-release) in HFrEF—it has never shown mortality benefit. 2
• Start at low doses and titrate every 2 weeks to target doses: carvedilol 25 mg twice daily, metoprolol succinate 200 mg once daily, or bisoprolol 10 mg once daily. 2

4. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone 25-50 mg once daily or eplerenone 25-50 mg once daily provide at least 20% mortality reduction and reduce sudden cardiac death. 1, 2
• Indicated for all symptomatic patients with LVEF ≤35% despite ACE-I/ARNI and beta-blocker therapy. 1
• Requires eGFR >30 mL/min/1.73 m² and potassium monitoring. 2
• Minimal blood pressure effect allows early initiation. 2

Diuretics for Volume Management

• Loop diuretics (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) are essential for congestion control but do not reduce mortality. 1, 2
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 2

Titration Strategy for Quadruple Therapy

Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 2

Recommended sequence: 2

1. Start SGLT2 inhibitor and MRA first (minimal BP effects)
2. Add beta-blocker if heart rate ≥70 bpm
3. Add or up-titrate ARNI/ACE-I/ARB
4. Continue aggressive up-titration toward target doses

Additional Therapies for Selected HFrEF Patients

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker dose. 1, 2
• Starting dose: 2.5-5 mg twice daily. 2
• Survival benefit is modest or negligible in the broad HFrEF population. 2

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 2
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily. 2
• May prolong survival but is inferior to ACE inhibitors for mortality. 2

Device Therapy for HFrEF

Implantable Cardioverter-Defibrillator (ICD)

Primary prevention: ICD is recommended to reduce sudden death and all-cause mortality in patients with symptomatic HF (NYHA class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, provided they are expected to survive >1 year with good functional status. 1, 2

• For ischemic cardiomyopathy: Class I, Level A recommendation (unless MI occurred within prior 40 days). 1
• For dilated cardiomyopathy: Class I, Level B recommendation. 1
• ICD implantation is not recommended within 40 days of MI as it does not improve prognosis during this period. 1

Secondary prevention: ICD is recommended for patients who have recovered from ventricular arrhythmia causing hemodynamic instability and are expected to survive >1 year with good functional status. 1

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 to improve symptoms and reduce morbidity and mortality. 1, 2

• QRS ≥150 msec with LBBB: Class I, Level A recommendation. 1
• QRS 130-149 msec with LBBB: Class I, Level B recommendation. 1
• CRT is contraindicated in patients with QRS duration <130 msec. 1
• CRT rather than RV pacing is recommended for patients with HFrEF who have an indication for ventricular pacing regardless of NYHA class. 1

Management of HFmrEF (LVEF 41-49%)

• Evidence for specific therapies is less robust than for HFrEF, with different levels of evidence across guidelines. 1, 3
• ACC/AHA/HFSA guidelines recommend SGLT2 inhibitors, ARBs, MRAs, and ARNIs with Level B-NR evidence. 1
• ESC guidelines suggest ACE-I, ARB, beta-blockers, MRA, and ARNI may be considered, but with Level C evidence. 1
• The distinction between HFmrEF and HFrEF is evolving, with increasing recognition that patients with LVEF 41-49% may benefit from therapies proven in HFrEF. 3

Management of HFpEF (LVEF ≥50%)

Treatment focuses on symptom relief through diuretics and optimal management of comorbidities, as evidence-based mortality-reducing therapies remain limited. 1, 4

• Diuretics for congestion control and symptom improvement. 1
• SGLT2 inhibitors may reduce HF hospitalization in selected patients. 1
• Spironolactone may be considered to reduce HF hospitalizations in selected patients. 1
• ARBs, MRAs, and ARNIs have weaker evidence in HFpEF compared to HFrEF. 1
• Aggressive management of hypertension, atrial fibrillation, coronary artery disease, diabetes, and other comorbidities is essential. 1, 6, 4

Prevention of Heart Failure

Primary Prevention (Stage A: At Risk for HF)

• Treatment of hypertension is recommended to prevent or delay the onset of HF and prolong life (Class I, Level A). 1
• Antihypertensive drugs, statins, SGLT2 inhibitors, and healthy lifestyle advice are recommended to prevent or delay HF onset. 1

Secondary Prevention (Stage B: Pre-HF/Asymptomatic LV Dysfunction)

• ACE inhibitor is recommended in patients with asymptomatic LV systolic dysfunction and history of MI to prevent or delay HF onset and prolong life (Class I, Level A). 1
• Beta-blocker is recommended in patients with asymptomatic LV systolic dysfunction and history of MI to prevent or delay HF onset and prolong life (Class I, Level B). 1

Critical Medications to Avoid in HFrEF

Diltiazem and verapamil are not recommended in HFrEF as they increase the risk of HF worsening and HF hospitalization (Class III, Level C). 1

The addition of an ARB (or renin inhibitor) to the combination of an ACE-I and an MRA is not recommended because of increased risk of renal dysfunction and hyperkalemia (Class III, Level C). 1

NSAIDs (including ibuprofen, etoricoxib, and topical formulations) should be avoided as they worsen HF symptoms, increase hospitalization risk, cause sodium/water retention, and interfere with guideline-directed medical therapy. 7

Do not combine ACE inhibitor with ARNI due to angioedema risk. 2

Managing Low Blood Pressure During GDMT Optimization

Never discontinue or reduce guideline-directed medical therapy for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2

For Symptomatic Hypotension (SBP <80 mmHg or Major Symptoms):

Step 1: Address reversible non-HF causes first: 2

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin)
• Discontinue other non-essential BP-lowering medications
• Evaluate for dehydration, infection, or acute illness

Step 2: Non-pharmacological interventions: 2

• Compression leg stockings for orthostatic symptoms
• Exercise and physical training programs
• Adequate salt and fluid intake if not volume overloaded
• Space out medication administration throughout the day

Step 3: If symptoms persist, reduce GDMT in this specific order: 2

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

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes simultaneously—start SGLT2 inhibitor, MRA, beta-blocker, and ARNI/ACE-I together as soon as possible after diagnosis. 2
• Accepting suboptimal doses—clinical trials demonstrated benefits at target doses, not low doses; aggressive up-titration is essential. 2
• Stopping medications for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms. 2
• Inadequate monitoring—check blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment. 2
• Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit. 2
• Discontinuing RAASi after hypotension or hyperkalemia—this is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 2

Monitoring Requirements

• Blood pressure, renal function, and electrolytes should be monitored at 1-2 weeks after each dose increment, with more frequent monitoring in elderly patients and those with chronic kidney disease. 2
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 2
• Potassium levels require close monitoring with MRAs; if hyperkalemia develops, consider potassium binders (e.g., patiromer) rather than discontinuing life-saving medications. 2
• Serial measurement of natriuretic peptide levels can be useful during diuretic titration to ensure congestion does not worsen. 2

Real-World Implementation Challenges

• Target doses of all recommended drugs were simultaneously achieved in only 1% of eligible patients in real-world registries, with discontinuation rates as high as 55% for ACE inhibitors. 2, 8
• Advanced age, female sex, lower blood pressure, and greater severity of HF are consistently associated with lower prescription or up-titration of GDMT. 2
• Most patients receive RASI and beta-blockers in the first months following HFrEF diagnosis, but use of ARNI (9.8-22%), MRA (35-46%), and SGLT2 inhibitors (19-30%) remains limited both in early and later time periods. 8