What is the recommended treatment regimen for patients presenting with heart failure?

Treatment Regimen for Heart Failure with Reduced Ejection Fraction

All patients with heart failure and reduced ejection fraction (HFrEF, LVEF ≤40%) should receive four foundational medication classes simultaneously: ACE inhibitors (or ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors, as this combination reduces mortality and hospitalization. 1

Initial Pharmacological Approach

ACE Inhibitors (First Pillar)

ACE inhibitors are the cornerstone of HFrEF therapy and should be initiated immediately in all patients with reduced left ventricular systolic function. 2, 1

Starting protocol:

• Begin with low doses: lisinopril 5 mg daily, enalapril 2.5-5 mg twice daily, or ramipril 2.5 mg daily 1
• Review and reduce diuretic doses 24 hours before initiation to avoid excessive hypotension 2, 1
• Consider starting in the evening when supine to minimize blood pressure effects 2
• Titrate upward every 1-2 weeks to target doses: lisinopril 20-35 mg daily, enalapril 10-20 mg twice daily, or ramipril 5-10 mg daily 1, 3
• Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, then every 6 months 2, 1

Critical safety measures:

• Avoid potassium-sparing diuretics during initiation 2
• Avoid NSAIDs throughout treatment 2
• Stop treatment if renal function deteriorates substantially 2
• High-dose ACE inhibitors (lisinopril 32.5-35 mg daily) reduce hospitalizations by 24% compared to low doses (2.5-5 mg daily), though mortality benefit is modest 4

Beta-Blockers (Second Pillar - Mandatory Co-Therapy)

Beta-blockers must be initiated in all stable patients already on ACE inhibitors and diuretics, ensuring no intravenous inotropic support requirements or marked fluid retention exist. 2, 1, 5

Evidence-based agents with proven mortality benefit (≥20% reduction):

• Bisoprolol: start 1.25 mg daily, target 10 mg daily 1, 5
• Metoprolol succinate CR: start 12.5-25 mg daily, target 200 mg daily 1, 5
• Carvedilol: start 3.125 mg twice daily, target 50 mg daily 1, 5
• Nebivolol: start low dose, target 10 mg daily 1

Titration strategy:

• Double the dose every 1-2 weeks if tolerated 1, 5
• If worsening symptoms occur, increase diuretics or ACE inhibitors first before reducing beta-blocker dose 5
• For hypotension, reduce vasodilators first rather than the beta-blocker 5
• Refer to specialist care for severe heart failure, bradycardia, low blood pressure, or suspected asthma/bronchial disease 5

Mineralocorticoid Receptor Antagonists (Third Pillar)

Add spironolactone or eplerenone for patients who remain symptomatic (NYHA Class III-IV) despite ACE inhibitor and beta-blocker therapy to reduce mortality and hospitalization. 2, 1, 6

Initiation protocol:

• Start only if serum potassium <5.0 mmol/L and creatinine <250 μmol/L (approximately <2.8 mg/dL) 2, 1, 5
• Begin with spironolactone 12.5-25 mg daily 1, 5
• Check potassium and creatinine after 4-7 days 2, 5
• Recheck every 5-7 days until potassium values are stable 2
• Reduce dose by 50% or stop if potassium persistently elevated 5

Critical warning: Never combine ACE inhibitor, ARB, and MRA due to increased risk of renal dysfunction and hyperkalemia 6

SGLT2 Inhibitors (Fourth Pillar)

SGLT2 inhibitors should be initiated early in all HFrEF patients regardless of diabetes status to reduce cardiovascular death and heart failure hospitalization. 1, 5

This represents the newest pillar of therapy with robust evidence for mortality and morbidity reduction 1

Diuretic Management (Symptomatic Relief)

Diuretics are essential for symptomatic treatment when fluid overload manifests as pulmonary congestion or peripheral edema, though they must always be combined with ACE inhibitors. 2, 6

Initial approach:

• Start with loop diuretics (furosemide, bumetanide) or thiazides 2
• If GFR <30 mL/min, avoid thiazides except when prescribed synergistically with loop diuretics 2

For insufficient response:

• Increase diuretic dose 2
• Combine loop diuretics and thiazides 2
• With persistent fluid retention: administer loop diuretics twice daily 2
• In severe chronic heart failure: add metolazone with frequent measurement of creatinine and electrolytes 2

Additional Pharmacological Considerations

Digoxin (Symptomatic Benefit Only)

Reserve digoxin for patients in sinus rhythm with persistent symptoms despite ACE inhibitor, beta-blocker, and diuretic treatment. 2, 5

• Usual dose: 0.25-0.375 mg daily if creatinine normal; 0.125-0.25 mg daily in elderly 2, 5
• No loading dose needed for chronic conditions 2
• Contraindications: bradycardia, second- or third-degree AV block, sick sinus syndrome, hypokalaemia, hypercalcaemia 2
• In atrial fibrillation with heart failure, digoxin combined with beta-blockade is superior to either agent alone 2

ARBs (Alternative to ACE Inhibitors)

ARBs should be considered only in patients who cannot tolerate ACE inhibitors (typically due to cough), though evidence for mortality reduction is less clear than with ACE inhibitors. 2

ARBs cause significantly less cough than ACE inhibitors 2

Device Therapy

Implantable cardioverter defibrillators (ICDs) are recommended for primary prevention in symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy in patients with ischemic heart disease or dilated cardiomyopathy. 1, 6

Important caveat: ICD implantation is not recommended within 40 days of MI as it does not improve prognosis 6

Cardiac resynchronization therapy (CRT) is recommended for symptomatic heart failure patients in sinus rhythm with QRS duration ≥150 msec, LBBB QRS morphology, and LVEF ≤35%. 6

Non-Pharmacological Management

Patient education about heart failure, symptom recognition, and self-management is essential. 2, 1, 6

Key lifestyle modifications:

• Daily physical activity in stable patients to prevent muscle deconditioning and improve exercise tolerance 2, 1, 6
• Control sodium intake, especially in severe heart failure 2, 1, 6
• Avoid excessive fluid intake in severe heart failure 2, 6
• Avoid excessive alcohol intake 2
• Daily self-weighing to detect fluid retention early 2
• Refrain from smoking; use nicotine replacement therapies if needed 2

Team-based care with cardiologists, primary care physicians, nurses, and pharmacists reduces mortality and hospitalization. 1, 5

Common Pitfalls to Avoid

Medications to avoid in HFrEF:

• Diltiazem or verapamil increase risk of heart failure worsening 6
• NSAIDs interfere with ACE inhibitor efficacy and worsen renal function 2

Underdosing remains a major problem: Most patients in clinical practice receive submaximal ACE inhibitor doses despite evidence that high doses (lisinopril 32.5-35 mg daily) provide greater benefit than low doses (2.5-5 mg daily) 4, 7. The ATLAS trial demonstrated that high-dose lisinopril reduced hospitalizations for heart failure by 24% compared to low doses 4. Over 90% of patients can tolerate titration to target doses when done carefully 8