What is the guideline‑based pharmacologic regimen (including drug choices, dosing, and titration) for an adult with chronic heart failure with reduced ejection fraction?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction

All adults with chronic HFrEF should receive four foundational drug classes—ACE inhibitor (or ARNI), beta-blocker, mineralocorticoid receptor antagonist, and diuretics as needed—initiated rapidly and titrated to target doses using forced-titration strategies proven in landmark trials. 1

Core Pharmacologic Regimen

First-Line: ACE Inhibitor or ARNI

• Start an ACE inhibitor immediately in every patient with reduced ejection fraction (≤40%), regardless of symptom severity, unless contraindicated. 1, 2
• Begin with low doses: enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg daily, or ramipril 1.25-2.5 mg daily. 1
• Titrate every 1-2 weeks to target doses: enalapril 10-20 mg twice daily, lisinopril 20-40 mg daily, or ramipril 10 mg daily. 3, 1
• Withhold or reduce diuretics for 24 hours before initiating ACE inhibitor to prevent first-dose hypotension. 1, 2
• Check blood pressure, creatinine, and potassium 1-2 weeks after each dose increase, at 3 months, then every 6 months. 3, 1

Alternative if ACE inhibitor not tolerated:

• Switch to ARB (valsartan or candesartan) if intolerable cough or angioedema occurs. 3, 1
• Use hydralazine plus isosorbide dinitrate if both ACE inhibitor and ARB are contraindicated. 3

Second-Line: Beta-Blocker

• Add beta-blocker (bisoprolol, carvedilol, or metoprolol succinate) only after patient is euvolemic and stable on ACE inhibitor therapy. 1, 2
• Start with very low doses: bisoprolol 1.25 mg daily, carvedilol 3.125 mg twice daily, or metoprolol succinate 12.5-25 mg daily. 3, 1
• Uptitrate every 1-2 weeks using "start-low, go-slow" approach. 3
• Target doses: bisoprolol 10 mg daily, carvedilol 25-50 mg twice daily (50 mg total daily for <85 kg, 100 mg for ≥85 kg), metoprolol succinate 200 mg daily. 1
• Either ACE inhibitor or beta-blocker can be started first with equivalent outcomes. 3

Third-Line: Mineralocorticoid Receptor Antagonist

• Add spironolactone 25 mg daily for patients who remain symptomatic (NYHA class II-IV) despite optimal ACE inhibitor and beta-blocker therapy. 1, 2
• Only initiate if serum potassium <5.0 mmol/L and adequate renal function (creatinine <2.5 mg/dL or eGFR >30 mL/min). 1
• Greatest mortality benefit occurs in NYHA class III-IV patients. 3, 1
• Check potassium and creatinine 4-6 days after starting; reduce dose by 50% or discontinue if potassium ≥5.5 mmol/L. 1

Diuretic Therapy (Symptomatic Relief)

• Loop diuretics (furosemide 20-40 mg daily initially) are essential for pulmonary congestion or peripheral edema but must always be combined with ACE inhibitor. 1, 2
• Titrate to lowest dose achieving euvolemia; diuretics provide symptom relief but no mortality benefit. 1
• If inadequate response: increase loop diuretic dose, give twice daily, or combine loop diuretic with thiazide. 3, 1
• Avoid thiazides if GFR <30 mL/min unless combined synergistically with loop diuretic. 3, 1
• For severe refractory fluid retention, add metolazone with frequent electrolyte and renal monitoring. 3, 1

Critical Monitoring Protocols

ACE Inhibitor Monitoring

• Avoid potassium-sparing diuretics and potassium supplements during ACE inhibitor initiation. 3, 1
• Discontinue ACE inhibitor if substantial renal function deterioration occurs. 3, 1
• Avoid NSAIDs—they worsen renal function, promote fluid retention, and blunt ACE inhibitor effects. 3, 1, 2

Beta-Blocker Monitoring

• Monitor for worsening heart failure symptoms, fluid retention, hypotension, and symptomatic bradycardia during titration. 1
• If symptoms worsen, optimize diuretic or ACE inhibitor first; reduce beta-blocker dose only if necessary. 1
• If hypotension occurs, reduce vasodilator dose first; beta-blocker reduction is secondary. 1
• Re-introduce and uptitrate beta-blocker when patient stabilizes. 1

Spironolactone Monitoring

• Measure potassium and creatinine 5-7 days after initiation and after each dose change. 3, 1
• Recheck every 5-7 days until potassium values are stable. 3

Forced-Titration Strategy (Critical Concept)

The mortality benefits proven in landmark trials were achieved using forced-titration strategies, not the subtarget dosing commonly used in practice. 3

• Uptitrate doses at planned intervals until target dose is achieved or intolerable adverse events occur. 3
• Asymptomatic vital sign or laboratory changes should not prevent uptitration to target doses. 3
• If medication is discontinued or dose decreased, this should be temporary—reinstitute and achieve target doses when possible. 3
• Patients maintained on subtarget doses for long periods have not been proven to have mortality benefit. 3

Additional Therapies

Digoxin

• Indicated for atrial fibrillation with any degree of symptomatic heart failure to control ventricular rate and improve symptoms. 3, 1
• In sinus rhythm, digoxin may improve clinical status in patients with persistent symptoms despite ACE inhibitor and diuretic therapy. 3, 1
• Typical dosing: 0.125-0.25 mg daily (lower dose 0.0625-0.125 mg in elderly with normal renal function). 1
• Combination of digoxin and beta-blocker appears superior to either alone. 3

Hydralazine-Isosorbide Dinitrate

• Recommended for African-American patients with NYHA class III-IV symptoms despite optimal therapy. 1
• Alternative for patients intolerant of both ACE inhibitors and ARBs. 3

Absolute Contraindications

ACE Inhibitors

• Bilateral renal artery stenosis 1
• History of angioedema with previous ACE inhibitor therapy 1
• Pregnancy 1

Beta-Blockers

• Asthma or severe bronchial disease 1
• Symptomatic bradycardia 1
• Severe hypotension 1

Mineralocorticoid Receptor Antagonists

• Baseline serum potassium >5.0 mmol/L 1
• Severe renal impairment (creatinine >2.5 mg/dL or eGFR <30 mL/min) 1

Common Pitfalls to Avoid

• Failure to uptitrate medications to target doses—most patients in practice receive only starting doses indefinitely, which lacks proven mortality benefit. 3, 2
• Using calcium channel blockers (diltiazem or verapamil) in HFrEF—they worsen heart failure outcomes. 2
• Combining ACE inhibitor, ARB, and MRA—increases risk of renal dysfunction and hyperkalemia. 2
• Inadequate diuresis in volume-overloaded patients before initiating beta-blocker. 2
• Starting beta-blocker before achieving euvolemia and ACE inhibitor stability. 1, 2

Duration of Therapy

Guideline-directed medical therapy (ACE inhibitor, beta-blocker, MRA) must be continued indefinitely, even if ejection fraction improves or symptoms resolve. 1

• Patients who discontinue therapy after LVEF recovery frequently experience relapse of left ventricular dysfunction and heart failure symptoms. 1
• Loop diuretics may be temporarily reduced or stopped in selected asymptomatic, euvolemic patients, but disease-modifying agents must be maintained. 1