What is the recommended first‑line outpatient treatment (medications and lifestyle measures) for a patient with newly diagnosed systolic heart failure (heart failure with reduced ejection fraction)?

First-Line Outpatient Treatment for Newly Diagnosed Systolic Heart Failure (HFrEF)

Start all four foundational medication classes simultaneously as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor if ARNI not tolerated), along with loop diuretics for volume management—this quadruple therapy provides approximately 73% mortality reduction over 2 years and adds 5.3 additional life-years compared to no treatment. 1

Immediate Pharmacological Therapy

The Four Foundational Medication Classes

1. SGLT2 Inhibitor (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily 1
• No dose titration required; maximal benefit achieved at starting dose 1
• Reduces 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), making it ideal for early initiation 1
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 1

2. Mineralocorticoid Receptor Antagonist (Start Simultaneously)

• Spironolactone 12.5-25 mg once daily, titrate to 50 mg daily at 8 weeks 1
• Provides at least 20% mortality reduction and reduces sudden cardiac death 2, 1
• Minimal blood pressure effect, allowing early initiation 1
• Requires eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L before starting 1
• Monitor potassium and creatinine at 1-2 weeks after initiation 1

3. Evidence-Based Beta-Blocker

• Use only one of three proven agents: carvedilol, metoprolol succinate, or bisoprolol 2, 1
• Carvedilol: Start 3.125 mg twice daily, target 25-50 mg twice daily 1
• Metoprolol succinate: Start 12.5-25 mg once daily, target 200 mg once daily 1
• Bisoprolol: Start 1.25 mg once daily, target 10 mg once daily 1
• Provides 34% mortality reduction, the highest relative risk reduction among the four medication classes 1
• Titrate every 2 weeks if heart rate ≥70 bpm and systolic BP >80 mmHg 1

4. Renin-Angiotensin System Inhibitor

• Preferred: Sacubitril/valsartan (ARNI) for NYHA class II-IV symptoms 1

  • Start 24/26 mg or 49/51 mg twice daily, target 97/103 mg twice daily 1
  • Provides at least 20% mortality reduction superior to ACE inhibitors 1
  • Do not combine with ACE inhibitor (risk of angioedema) 1
  • Requires 36-hour washout period after stopping ACE inhibitor 1

• Alternative: ACE Inhibitor if ARNI not tolerated 2

  • Start low dose, build up to target doses shown effective in trials 2
  • Avoid excessive diuresis before starting; may reduce or withhold diuretics for 24 hours 2
  • Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 2

Loop Diuretics for Volume Management

• Essential for congestion control but do not reduce mortality 1, 3
• 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
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 1
• High-dose loop diuretic treatment is superior to low-dose for hospitalized patients 3

Titration Strategy

Sequence for Optimal Uptitration:

1. Start SGLT2 inhibitor and MRA first (minimal BP effects) 1
2. Add beta-blocker if heart rate >70 bpm 1
3. Initiate or uptitrate ARNI/ACE inhibitor 1
4. Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose achieved 1

Essential Lifestyle Modifications

Patient Education

• Explain what heart failure is and why symptoms occur 2
• Teach recognition of worsening symptoms (increased dyspnea, weight gain >2-3 lbs in 1 day or >5 lbs in 1 week) 2
• Daily self-weighing to detect fluid retention early 2
• Importance of medication adherence 2

Dietary Modifications

• Sodium restriction: Control sodium intake when necessary, especially in severe heart failure 2
• Avoid excessive fluid intake in severe HF 2
• Avoid excessive alcohol intake 2

Physical Activity

• Do not encourage rest in stable conditions 2
• Daily physical and leisure activities in stable patients to prevent muscle deconditioning 2
• Exercise training programs in stable NYHA II-III patients 2

Smoking Cessation

• Refrain from smoking; use nicotine replacement therapies if needed 2

Managing Low Blood Pressure During Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 1

If symptomatic hypotension occurs (SBP <80 mmHg or major symptoms):

1. Address reversible non-HF causes first: stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, evaluate for dehydration/infection 1
2. Non-pharmacological interventions: compression leg stockings for orthostatic symptoms, adequate salt and fluid intake if not volume overloaded 1
3. If symptoms persist: reduce GDMT in this order—if heart rate >70 bpm, reduce ACEi/ARB/ARNI dose first; if heart rate <60 bpm, reduce beta-blocker dose first; always maintain SGLT2 inhibitor and MRA 1

Monitoring Requirements

Initial Monitoring (First 3 Months):

• Blood pressure, heart rate, and symptoms at each visit 2, 1
• Renal function and electrolytes at 1-2 weeks after each dose increment 2, 1
• More frequent monitoring in elderly patients and those with chronic kidney disease 1

Acceptable Changes During Optimization:

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1
• Potassium levels require close monitoring with MRAs; use potassium binders (patiromer) rather than discontinuing therapy if hyperkalemia develops 1

Long-Term Monitoring:

• Blood pressure, renal function, and electrolytes at 3 months, then every 6 months 2

Critical Contraindications and Medications to Avoid

Absolute Contraindications:

• Do not combine ACE inhibitor with ARNI (risk of angioedema) 1
• Do not use triple combination of ACE inhibitor + ARB + MRA (extreme hyperkalemia and renal dysfunction risk) 1
• Avoid diltiazem or verapamil in HFrEF (increase risk of worsening heart failure and hospitalization) 1

Medications to Avoid:

• Non-steroidal anti-inflammatory drugs (NSAIDs) 2
• Non-evidence-based beta-blockers (only use carvedilol, metoprolol succinate, or bisoprolol) 1
• Alpha-blockers for benign prostatic hyperplasia (interfere with GDMT optimization) 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

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

Digoxin:

• Indicated in atrial fibrillation with any degree of symptomatic heart failure to slow ventricular rate 2
• In sinus rhythm, improves clinical status in patients with persisting symptoms due to LV systolic dysfunction 2

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—start simultaneously, not sequentially 1
2. Accepting suboptimal doses—clinical trials demonstrated benefits at target doses, not low doses 1
3. 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 1
4. Inadequate monitoring—failure to check renal function and electrolytes leads to preventable complications 1
5. Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, or bisoprolol reduce mortality 1
6. Down-titrating GDMT for modest creatinine increases—discontinuing RAASi after renal function changes is associated with two to fourfold higher risk of adverse events 1

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Recommended for primary prevention in symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy, expected to survive >1 year with good functional status 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