What guideline‑directed medications should be started in a patient with chronic systolic heart failure, including African‑American considerations?

Guideline-Directed Medical Therapy for Chronic Systolic Heart Failure

All patients with chronic systolic heart failure should be started on quadruple therapy consisting of an ACE inhibitor (or ARNI/ARB), a beta-blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor, initiated simultaneously or in rapid sequence at low doses with uptitration to target, plus diuretics for fluid management. 1, 2

Initial Medication Selection and Sequencing

First-Line Renin-Angiotensin System Inhibition

• ACE inhibitors are the foundational first-line therapy for all patients with reduced left ventricular systolic function, regardless of symptom severity, and should be started immediately unless contraindicated. 3, 1
• For patients without fluid retention, start ACE inhibitor monotherapy at low doses: enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg daily, or ramipril 1.25-2.5 mg daily. 1
• For patients with fluid retention or congestion, start ACE inhibitor plus loop diuretic (furosemide 20-40 mg daily) simultaneously. 1
• ARNI (sacubitril/valsartan) is the preferred renin-angiotensin system inhibitor for NYHA class II-III symptoms to reduce morbidity and mortality, superior to ACE inhibitors alone. 2
• If ACE inhibitor causes intolerable cough or angioedema, switch to an angiotensin receptor blocker (ARB) such as valsartan or candesartan. 3, 1, 2

Beta-Blocker Initiation

• Beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) are recommended for all patients with current or previous symptoms of systolic heart failure once euvolemic and stable on ACE inhibitor therapy. 3, 2
• Start with very low doses and uptitrate gradually every 1-2 weeks if the preceding dose was well tolerated: bisoprolol 1.25 mg daily, carvedilol 3.125 mg twice daily, or metoprolol succinate 12.5-25 mg daily. 3
• Patients should be on background ACE inhibitor therapy and relatively stable without need for intravenous inotropic therapy or marked fluid retention before beta-blocker initiation. 3
• Target doses proven effective in trials: bisoprolol 10 mg daily, carvedilol 50 mg daily, metoprolol succinate 200 mg daily. 3

Mineralocorticoid Receptor Antagonist Addition

• Spironolactone is recommended for advanced heart failure (NYHA class III-IV) in addition to ACE inhibition and diuretics to improve survival and morbidity. 3
• Add spironolactone 25 mg daily if patient has severe heart failure despite ACE inhibitor/diuretics, with serum potassium <5.0 mmol/L and creatinine <250 mmol/L. 3
• For NYHA class II-IV symptoms, use MRA (spironolactone or eplerenone) if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L. 2

SGLT2 Inhibitor Therapy

• SGLT2 inhibitors are recommended for all patients with systolic heart failure regardless of diabetes status to reduce hospitalizations and cardiovascular mortality. 2
• This represents the most contemporary addition to guideline-directed medical therapy and should be initiated as part of quadruple therapy. 2

Diuretic Management

Symptomatic Fluid Control

• Diuretics are essential for symptomatic treatment when fluid overload manifests as pulmonary congestion or peripheral edema, resulting in rapid improvement of dyspnea and increased exercise tolerance. 3
• Loop diuretics or thiazides should always be administered in combination with ACE inhibitors if possible. 3
• If glomerular filtration rate <30 mL/min, do not use thiazides except synergistically with loop diuretics. 3

Escalation for Insufficient Response

• For inadequate diuretic response, increase the dose or administer loop diuretics twice daily. 3
• Combine loop diuretics and thiazides for persistent fluid retention. 3
• In severe chronic heart failure, add metolazone with frequent measurement of creatinine and electrolytes. 3

Critical Monitoring and Titration Protocols

ACE Inhibitor Monitoring

• Check baseline blood pressure, serum creatinine, potassium, and sodium before starting ACE inhibitor therapy. 1
• Avoid excessive diuresis before ACE inhibitor treatment; reduce or withhold diuretics for 24 hours if being used. 3
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and subsequently at 6-month intervals. 3, 1
• If renal function deteriorates substantially, stop ACE inhibitor treatment. 3
• Avoid potassium-sparing diuretics during initiation of ACE inhibitor therapy. 3

Beta-Blocker Monitoring

• Monitor for evidence of heart failure symptoms, fluid retention, hypotension, and symptomatic bradycardia during titration. 3
• If worsening symptoms occur, first increase the dose of diuretics or ACE inhibitor; temporarily reduce beta-blocker dose only if necessary. 3
• If hypotension develops, first reduce the dose of vasodilators; reduce beta-blocker dose only if necessary. 3
• Always consider reintroduction and/or uptitration of beta-blocker when patient becomes stable. 3

Spironolactone Monitoring

• Check serum potassium and creatinine after 4-6 days of spironolactone initiation. 3
• If serum potassium ≥5.5 mmol/L at any time, reduce dose by 50% or stop if potassium continues rising. 3

Special Considerations for African-American Patients

Hydralazine-Isosorbide Dinitrate Combination

• The combination of hydralazine and isosorbide dinitrate should be considered for African-American patients who cannot tolerate ACE inhibitors or ARBs. 1
• This combination may provide additional benefit in African-American patients as adjunctive therapy to standard guideline-directed medical therapy. 1

Absolute Contraindications and Critical Pitfalls

ACE Inhibitor Contraindications

• Bilateral renal artery stenosis, history of angioedema with previous ACE inhibitor therapy, and pregnancy are absolute contraindications. 1

Beta-Blocker Contraindications

• Asthma bronchiale, severe bronchial disease, and symptomatic bradycardia or hypotension are contraindications. 3

Medications to Avoid

• Avoid NSAIDs, which worsen renal function and promote fluid retention, particularly in patients on ACE inhibitors or with fluid retention. 3, 1
• Avoid calcium channel blockers except amlodipine for specific indications, as they worsen heart failure outcomes. 1
• Avoid potassium supplements during ACE inhibitor initiation. 1

Additional Pharmacotherapy

Cardiac Glycosides

• Digoxin is indicated for atrial fibrillation with any degree of symptomatic heart failure to slow ventricular rate and improve ventricular function and symptoms. 3
• In sinus rhythm, digoxin is recommended to improve clinical status in patients with persisting heart failure symptoms despite ACE inhibitor and diuretic treatment. 3
• Usual daily dose of oral digoxin is 0.125-0.25 mg if serum creatinine is normal (in elderly 0.0625-0.125 mg). 3

Vasodilator Agents

• There is no specific role for direct-acting vasodilator agents in treatment of chronic heart failure, though they may be used as adjunctive therapy for angina or concomitant hypertension. 3

Contemporary Treatment Paradigm

Simultaneous Initiation Strategy

• Start guideline-directed medical therapy simultaneously or in rapid sequence at the time of heart failure diagnosis, including during hospitalization, and do not delay initiation waiting for "stability." 2
• Never discontinue guideline-directed medical therapy even if symptoms resolve and ejection fraction improves, as 40% of patients relapse within 6 months of medication withdrawal. 2
• Continue all guideline-directed medical therapy indefinitely to prevent relapse of heart failure and left ventricular dysfunction, even in asymptomatic patients. 2