What is the recommended Guideline-Directed Medical Therapy (GDMT) for patients with ischemic cardiomyopathy and combined heart failure?

Guideline-Directed Medical Therapy for Ischemic Cardiomyopathy with Heart Failure

For patients with ischemic cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), the foundational GDMT consists of four medication classes that must be initiated and uptitrated to target doses: ACE inhibitors (or ARBs/ARNI), evidence-based beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. 1

Core Medication Classes

Renin-Angiotensin System Inhibition

• ACE inhibitors are Class I, Level A recommendations for all patients with ischemic cardiomyopathy and reduced ejection fraction to prevent symptomatic heart failure and reduce mortality 1
• ARBs serve as appropriate alternatives when ACE inhibitors cause intolerable cough or angioedema 1, 2
• Sacubitril/valsartan (ARNI) demonstrated superiority over enalapril in the PARADIGM-HF trial, reducing cardiovascular death or heart failure hospitalization by 20% (HR 0.80,95% CI 0.73-0.87, p<0.0001) and improving all-cause mortality (HR 0.84,95% CI 0.76-0.93, p=0.0009) 3
• Begin with low doses and uptitrate to target doses proven in clinical trials, not based solely on symptomatic improvement 2
• Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and subsequently at 6-month intervals 2

Beta-Blockers

• Evidence-based beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) are Class I, Level B recommendations for all patients with ischemic cardiomyopathy and reduced ejection fraction 1, 2
• These agents should be added to ACE inhibitors/ARBs and diuretics for all patients with stable heart failure and reduced ejection fraction in NYHA class II-IV 2
• Initiate at low doses after optimization of volume status and discontinuation of intravenous agents 1
• Continue beta-blockers during hospitalization except in cases of hemodynamic instability or contraindications 1

Mineralocorticoid Receptor Antagonists

• Spironolactone is recommended for advanced heart failure (NYHA class III-IV) in addition to ACE inhibitors and diuretics to improve survival and morbidity 2
• Avoid potassium-sparing diuretics during ACE inhibitor initiation to prevent hyperkalemia 2
• Monitor renal function and electrolytes closely, recognizing that initial rises in creatinine may be expected and do not necessarily require discontinuation 1

SGLT2 Inhibitors

• SGLT2 inhibitors represent a newer Class I recommendation for patients with HFrEF, based on contemporary guidelines 1
• These agents reduce heart failure hospitalizations and cardiovascular mortality independent of diabetes status 1

Diuretic Therapy

• Loop diuretics are Class I, Level C recommendations for immediate relief of symptoms due to volume overload 1
• When hospitalized with fluid overload, patients should receive intravenous loop diuretics at doses greater than or equal to their chronic oral daily dose, then serially adjusted 1
• For inadequate diuresis, increase loop diuretic doses or add a second diuretic such as a thiazide 1, 2
• Thiazides should be avoided if glomerular filtration rate is less than 30 mL/min except when prescribed synergistically with loop diuretics 2

Additional Pharmacologic Considerations

Vericiguat

• Vericiguat may be considered (Class IIb) for higher-risk patients with worsening HFrEF who have LVEF <45%, NYHA class II-IV, elevated natriuretic peptides, and recent heart failure worsening despite GDMT 1
• The VICTORIA trial showed a 10% relative risk reduction in cardiovascular death or heart failure hospitalization (HR 0.90, p=0.019), though patients in the highest quartile of NT-proBNP (>5314 pg/mL) did not benefit 1

Medications to Avoid

• Non-dihydropyridine calcium channel blockers are Class III: Harm in patients with low LVEF and no symptoms after MI due to negative inotropic effects 1
• NSAIDs should be avoided as they interfere with ACE inhibitor efficacy 2

Device Therapy

Implantable Cardioverter-Defibrillators

• ICD therapy is Class I, Level A for primary prevention of sudden cardiac death in patients with ischemic cardiomyopathy at least 40 days post-MI with LVEF ≤35% and NYHA class II or III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival >1 year 1
• ICD therapy is Class I, Level B for patients at least 40 days post-MI with LVEF ≤30% and NYHA class I symptoms while receiving GDMT 1
• ICDs are of uncertain benefit (Class IIb) in patients with high risk of nonsudden death such as frequent hospitalizations, frailty, or severe comorbidities 1

Cardiac Resynchronization Therapy

• CRT is Class I, Level A for patients with LVEF ≤35%, sinus rhythm, LBBB with QRS ≥150 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT 1
• CRT is Class IIa, Level B for patients with LVEF ≤35%, sinus rhythm, LBBB with QRS 120-149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT 1
• CRT can be useful (Class IIa) for patients with LVEF ≤35%, sinus rhythm, non-LBBB pattern with QRS ≥150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT 1

Revascularization

• Coronary revascularization is Class IIa, Level C for patients with coronary artery disease in whom angina or demonstrable myocardial ischemia is present despite GDMT 1
• CABG is recommended (Class I) for patients with left main CAD and moderate or severe LV dysfunction, showing long-term reduction in all-cause, cardiovascular, and heart failure hospitalizations 1
• The survival benefit is greater in those with more advanced ischemic cardiomyopathy (lower EF or 3-vessel disease) and diminishes with increasing age 1

Uptitration Strategy

A systematic approach to GDMT optimization is critical, as achieving target doses is associated with improved outcomes but occurs in only 1% of eligible patients simultaneously across all medication classes 1:

• Start with low doses and alternate adjustments of different medication classes (especially ACE inhibitors/ARBs and beta-blockers) 1
• Monitor vital signs closely before and during uptitration, including postural changes in blood pressure or heart rate 1
• Patients with elevated or normal blood pressure and heart rate may tolerate faster incremental increases in dosages 1
• Reassure patients that symptoms of fatigue and weakness with dosage increases are often transient and usually resolve within a few days 1
• Discourage sudden spontaneous discontinuation of GDMT medications without discussion with managing clinicians 1
• Consider temporary adjustments in dosages during acute episodes of noncardiac illnesses 1

Common Pitfalls

Clinical inertia remains the primary barrier to optimal GDMT implementation 1:

• Only 15-30% of patients achieve target doses of ACE inhibitors, ARBs, beta-blockers, or sacubitril/valsartan over 12 months 4
• Discontinuation rates are high: 55% for ACE inhibitors, 33% for ARBs, 24% for beta-blockers, and 27% for sacubitril/valsartan 1
• Patients seen in heart failure clinics have significantly higher GDMT initiation rates (HR 1.54-2.49 across medication classes) compared to general cardiology or primary care 5
• A simple GDMT score ≥5 (based on combination and dosage of medications, 0-9 points) is associated with reduced all-cause death and heart failure readmission 6

Vulnerable populations require more frequent monitoring but may accrue considerable benefits from GDMT 1:

• Elderly patients, those with lower blood pressure, advanced renal dysfunction, or severe hypotension require more gradual dose changes 1
• Female sex, advanced age, lower blood pressure, and greater severity of heart failure are consistently associated with lower prescription or uptitration of GDMT 1