How should dilated cardiomyopathy with reduced ejection fraction be managed?

Management of Dilated Cardiomyopathy with Reduced Ejection Fraction

All patients with dilated cardiomyopathy and reduced ejection fraction (HFrEF, LVEF ≤40%) should immediately start four foundational medication classes simultaneously: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), an evidence-based beta-blocker, and an ARNI (or ACE inhibitor if ARNI not tolerated), along with loop diuretics for volume management—this quadruple therapy provides approximately 61% reduction in all-cause mortality and adds 5.3 life-years compared to no treatment. 1

Core Pharmacological Therapy: The Four Pillars

1. SGLT2 Inhibitors (Start First)

• Initiate dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily immediately at diagnosis. 1 No dose titration is required—the 10 mg dose provides maximal benefit without dose-response relationship. 1
• SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalization by 18-25% regardless of diabetes status, with benefits occurring within weeks of initiation. 1
• These agents have minimal blood pressure effects (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months), making them ideal first agents even in patients with borderline blood pressure. 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 Antagonists (Start Simultaneously)

• Start spironolactone 12.5-25 mg once daily, then up-titrate to target dose of 50 mg daily at 8 weeks if tolerated. 1
• MRAs provide at least 20-30% mortality reduction and reduce sudden cardiac death when added to other guideline-directed medical therapy. 1
• MRAs have minimal blood pressure effects, allowing early initiation even in patients with low-normal blood pressure. 1
• Require eGFR >30 ml/min/1.73 m² and baseline potassium <5.0 mEq/L before initiating. 1
• If gynecomastia develops (occurs in ~10% of patients), switch to eplerenone rather than discontinuing therapy. 1

3. Evidence-Based Beta-Blockers

• Use only carvedilol, metoprolol succinate, or bisoprolol—these three agents reduce mortality by 34%, the highest relative risk reduction among the four medication classes. 1
• Starting doses: carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily. 1
• Target doses: carvedilol 25 mg twice daily (50 mg twice daily if >85 kg), metoprolol succinate 200 mg once daily, or bisoprolol 10 mg once daily. 1
• Up-titrate every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 1
• Never use diltiazem or verapamil in HFrEF—these non-dihydropyridine calcium channel blockers increase risk of worsening heart failure and hospitalization and are absolutely contraindicated. 1

4. Angiotensin Receptor-Neprilysin Inhibitor (ARNI) or ACE Inhibitor

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors, providing at least 20% mortality reduction superior to enalapril. 1
• For symptomatic patients (NYHA class II-IV), start sacubitril/valsartan 49/51 mg twice daily, then up-titrate to target dose of 97/103 mg twice daily over 4-8 weeks. 1
• For asymptomatic patients (NYHA class I), continue ACE inhibitor at target dose rather than switching to ARNI—the FDA authorizes sacubitril/valsartan only for NYHA class II-IV patients, and PARADIGM-HF trial excluded asymptomatic patients. 1
• If using ACE inhibitor, enalapril target dose is 10-20 mg twice daily. 2
• Never combine ACE inhibitor with ARNI due to angioedema risk; allow 36-hour washout period when switching from ACE inhibitor to ARNI. 1
• Never combine ACE inhibitor + ARB + MRA together due to extreme hyperkalemia and renal dysfunction risk. 1

Diuretic Therapy for Volume Management

• Loop diuretics are essential for congestion control but do not reduce mortality. 1
• 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
• Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 1
• In stable patients without congestive signs, cautiously decrease diuretic dose to minimize blood pressure-lowering effects and facilitate GDMT optimization. 1

Sequencing Strategy: How to Start All Four Classes

Start SGLT2 inhibitor and MRA first (same day) since they have minimal blood pressure effects, then add beta-blocker within 1-2 weeks if heart rate >70 bpm, then add low-dose ARNI or ACE inhibitor. 1

• Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 1
• Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment. 1
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation—changes in kidney function during GDMT optimization must be interpreted in the context of decongestion. 1

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

For Symptomatic Hypotension (SBP <80 mmHg or Major Symptoms):

Step 1: Address reversible non-HF causes first

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) immediately—these are non-essential medications that compromise GDMT optimization. 1
• Discontinue other non-essential blood pressure-lowering medications. 1
• Evaluate for dehydration, infection, or acute illness. 1

Step 2: Non-pharmacological interventions

• Compression leg stockings for orthostatic symptoms. 1
• Exercise and physical training programs. 1
• Adequate salt and fluid intake if not volume overloaded. 1
• Space out medication administration throughout the day. 1

Step 3: If symptoms persist, reduce GDMT in this specific order

• If heart rate >70 bpm, reduce ACE inhibitor/ARB/ARNI dose first. 1
• If heart rate <60 bpm, reduce beta-blocker dose first. 1
• Always maintain SGLT2 inhibitor and MRA at full doses (minimal blood pressure effects). 1

Critical caveat: Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 1

Additional Therapies for Selected Patients

Ivabradine

• Add ivabradine only if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker dose and patient remains symptomatic (NYHA class II-IV). 3
• Starting dose: 2.5-5 mg twice daily, titrated to maintain resting heart rate between 50-60 bpm. 3
• Ivabradine reduces hospitalization for worsening heart failure (HR 0.74,95% CI 0.66-0.83) but has no favorable effect on cardiovascular mortality. 3
• Survival benefit is modest or negligible in the broad HFrEF population—this is an add-on therapy, not a substitute for the four foundational classes. 1

Hydralazine/Isosorbide Dinitrate

• Indicated specifically 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, titrated to target doses of 75 mg and 40 mg three times daily respectively. 1
• Can prolong survival but may be inferior to ACE inhibitors for mortality in non-Black populations. 1

Device Therapy

Implantable Cardioverter-Defibrillator (ICD)

• ICD is indicated for primary prevention in patients with symptomatic HF (NYHA class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, who are expected to survive >1 year with good functional status. 1, 4
• ICD is indicated for secondary prevention in patients who have recovered from ventricular arrhythmia causing hemodynamic instability. 1
• Patients with severely reduced ejection fraction have high risk for sudden cardiac death due to ventricular arrhythmias. 4

Cardiac Resynchronization Therapy (CRT)

• CRT is 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
• CRT has Class I indication if QRS ≥130 msec and LBBB in sinus rhythm. 1

Monitoring Requirements

• Monitor blood pressure, heart rate, renal function (creatinine, eGFR), and electrolytes (potassium) at 1-2 weeks after each dose increment. 1
• More frequent monitoring is required in elderly patients and those with chronic kidney disease. 1
• If hyperkalemia develops (potassium >5.5 mEq/L), consider potassium binders like patiromer rather than discontinuing life-saving MRA therapy. 1
• Serial monitoring of natriuretic peptide levels (BNP or NT-proBNP) can be useful during diuretic titration to ensure congestion does not worsen. 1

Referral to Heart Failure Specialist

• Refer when patient remains symptomatic despite optimal medical therapy at target doses. 5
• Refer when considering mechanical circulatory support or transplantation evaluation. 1
• Refer for advanced heart failure management when patient has persistent NYHA class III-IV symptoms despite quadruple therapy. 1
• Enrollment in a multidisciplinary heart failure management program reduces hospitalization risk and improves survival. 4

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes simultaneously—start SGLT2 inhibitor and MRA on day one of diagnosis. 1
• Accepting suboptimal doses due to unfounded blood pressure concerns—clinical trials demonstrated benefits at target doses, not low doses. 1
• 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 arms in clinical trials. 1
• Using non-evidence-based beta-blockers (atenolol, propranolol, labetalol) instead of the three proven agents (carvedilol, metoprolol succinate, bisoprolol). 1
• Inadequate monitoring leading to preventable hyperkalemia or worsening renal function—check labs 1-2 weeks after each dose change. 1
• Premature discontinuation of medications due to low blood pressure when mortality benefits of GDMT outweigh risks. 4
• Underutilization of GDMT despite proven benefits—in real-world registries, target doses of all recommended drugs were simultaneously achieved in only 1% of eligible patients. 1

Expected Outcomes with Optimal Therapy

• The combination of all four foundational medication classes reduces all-cause mortality by 61% (HR 0.39,95% CI 0.32-0.49) and provides approximately 5.3 additional life-years compared to no treatment. 1
• Each medication class contributes independently: beta-blockers provide 34% mortality reduction, ARNI provides 20% mortality reduction superior to ACE inhibitors, MRAs provide 20-30% mortality reduction, and SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalization by 18-25%. 1
• Even in patients with severely reduced ejection fraction (LVEF ≤19%), median survival on medical therapy alone exceeds 7 years. 6