What are the recommended maintenance medications for a patient with dilated cardiomyopathy and reduced ejection fraction?

Maintenance Medications for Dilated Cardiomyopathy with Reduced Ejection Fraction

All patients with dilated cardiomyopathy and reduced ejection fraction should be started on quadruple therapy consisting of an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), an evidence-based beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), initiated simultaneously at low doses within 2-4 weeks of diagnosis, along with loop diuretics for volume management. 1, 2, 3

The Four Foundational Medication Classes

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily should be initiated immediately as they reduce cardiovascular death and heart failure hospitalization by approximately 25-30% regardless of diabetes status. 1, 2, 3
• These agents have minimal blood pressure effects (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making them ideal first-line agents. 2
• Benefits occur within weeks of initiation with no dose titration required. 2, 3
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin or ≥20 ml/min/1.73 m² for dapagliflozin. 2

2. Mineralocorticoid Receptor Antagonists (Start First)

• Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily provide at least 20% mortality reduction and reduce sudden cardiac death. 1, 2
• Target dose: spironolactone 50 mg daily or eplerenone 50 mg daily. 1
• These agents have minimal blood pressure effects, allowing early initiation alongside SGLT2 inhibitors. 2, 3
• Require eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L before initiation. 2
• Critical: Do not withdraw spironolactone once ejection fraction improves—58% of patients relapse after withdrawal compared to only 13% who continue therapy. 4

3. Evidence-Based Beta-Blockers (Start 1-2 Weeks Later)

• Only three beta-blockers reduce mortality: carvedilol, metoprolol succinate (extended-release), or bisoprolol. 1, 2
• Starting doses: carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily. 2, 3
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg once daily, or bisoprolol 10 mg once daily. 2
• These agents provide at least 20% mortality reduction and decrease sudden cardiac death. 1, 2, 3

4. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - Preferred Over ACE Inhibitors

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily is preferred over ACE inhibitors or ARBs, providing at least 20% additional mortality reduction. 1, 2, 3
• Target dose: 97/103 mg twice daily. 2, 3
• Start 1-2 weeks after beta-blocker initiation. 3, 5
• Never combine with ACE inhibitors due to angioedema risk; must wait 36 hours after stopping ACE inhibitor before starting ARNI. 2
• If ARNI not tolerated, use ACE inhibitor (e.g., enalapril 2.5-5 mg twice daily, target 10-20 mg twice daily) or ARB (e.g., losartan 25-50 mg daily, target 150 mg daily). 1

Diuretics for Volume Management

• Loop diuretics are essential for congestion control but do not reduce mortality. 1, 2, 3
• Starting doses: 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, 3
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state. 1, 2

Rapid Sequencing Strategy (Evidence-Based Approach)

Week 1: Start SGLT2 inhibitor + MRA simultaneously (minimal BP effects allow safe co-initiation). 2, 3, 5

Week 2-3: Add evidence-based beta-blocker at low dose. 3, 5

Week 3-4: Initiate ARNI (sacubitril/valsartan) at low dose. 3, 5

Weeks 4-12: Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose achieved. 1, 2, 3

Additional Therapies for Specific Subgroups

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker. 1, 2, 6
• Starting dose: 2.5-5 mg twice daily, target 7.5 mg twice daily. 2, 6
• Reduces heart failure hospitalization but has minimal or no mortality benefit. 1, 6, 7

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy. 1, 2
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily. 2
• Target dose: hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily. 2

Digoxin

• Only recommended for atrial fibrillation rate control or persistent NYHA class III-IV symptoms despite optimal GDMT. 1, 7
• Has minimal effect on disease progression and no mortality benefit. 1

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for LVEF ≤35%, NYHA class II-III symptoms, and expected survival >1 year with good functional status after ≥3 months of optimal medical therapy. 1, 2, 3
• Also indicated for secondary prevention after cardiac arrest or hemodynamically unstable ventricular tachycardia. 1, 2
• Must wait at least 40 days post-MI before ICD implantation. 1

Cardiac Resynchronization Therapy (CRT)

• Indicated for LVEF ≤35%, NYHA class II-IV symptoms, sinus rhythm, and QRS ≥150 msec with left bundle branch block (LBBB) morphology. 1, 2, 3
• Improves symptoms, reduces hospitalizations, and reduces mortality. 1, 2

Critical Contraindications and Medications to Avoid

• Never use diltiazem or verapamil (non-dihydropyridine calcium channel blockers)—they increase risk of worsening heart failure and hospitalization. 1, 2
• Avoid combining ACE inhibitor with ARNI due to angioedema risk. 2
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk. 2
• Stop alpha-blockers (tamsulosin, doxazosin) as they interfere with GDMT optimization by causing hypotension. 2
• Avoid NSAIDs and most antiarrhythmic drugs as they adversely affect clinical status. 1

Managing Low Blood Pressure During Optimization

• Do not withhold or down-titrate GDMT for asymptomatic hypotension with adequate perfusion. 2
• GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2
• First address reversible non-HF causes: stop alpha-blockers, evaluate for dehydration, infection, or other acute illness. 2
• Start SGLT2 inhibitor and MRA first (minimal BP effects), then add low-dose beta-blocker or ARNI. 2, 3
• Consider spacing out medication administration throughout the day. 2

Monitoring Requirements

• Monitor blood pressure, renal function (creatinine, eGFR), and electrolytes (potassium) at 1-2 weeks after each dose increment. 2
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 2
• If hyperkalemia develops (K+ >5.5 mEq/L), consider potassium binders like patiromer rather than discontinuing life-saving MRA therapy. 2
• More frequent monitoring required in elderly patients and those with chronic kidney disease. 2

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start simultaneously within 2-4 weeks, not sequentially over 6+ months. 2, 3, 5
• Accepting suboptimal doses—low doses of all four classes provide more benefit than target doses of only one or two classes. 2, 5
• Stopping medications for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment. 2
• Using non-evidence-based beta-blockers (atenolol, metoprolol tartrate)—only carvedilol, metoprolol succinate, and bisoprolol reduce mortality. 1, 2
• Withdrawing spironolactone after ejection fraction improves—this leads to 58% relapse rate. 4
• Inadequate follow-up—early follow-up within 7-14 days after medication adjustments is essential. 3

Expected Outcomes with Optimal Therapy

• Quadruple therapy provides approximately 73% mortality reduction over 2 years compared to no treatment. 2
• Median survival exceeds 7 years even in patients with LVEF ≤19% on optimal medical therapy. 8
• Benefits occur rapidly—SGLT2 inhibitors show benefits within weeks, not months. 2, 3