What is the initial approach to Guideline-Directed Medical Therapy (GDMT) for heart failure treatment?

Initial Approach to Guideline-Directed Medical Therapy (GDMT) for Heart Failure with Reduced Ejection Fraction

The initial approach to GDMT for heart failure with reduced ejection fraction (HFrEF) should start with simultaneous or rapid sequential initiation of four core medication classes: SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRAs), beta-blockers, and renin-angiotensin system inhibitors or angiotensin receptor-neprilysin inhibitors (ARNi). 1

Core Medication Strategy

First-Line Medications

• Begin with SGLT2 inhibitors and MRAs as they have minimal effect on blood pressure but provide rapid benefits 2
• SGLT2 inhibitors are effective with moderate kidney dysfunction (eGFR ≥30 ml/min/1.73 m² for empagliflozin, ≥20 ml/min/1.73 m² for dapagliflozin) and require no dose adjustment or up-titration 1
• MRAs should be initiated at low doses with monitoring of potassium and renal function 1

Second-Line Medications

• Beta-blockers should be started at low doses if heart rate >70 bpm, with preference for evidence-based options (metoprolol succinate, carvedilol, bisoprolol) 1, 3
• ACEi/ARB or ARNi should be initiated at low doses with careful blood pressure monitoring 1
• Consider starting with sacubitril/valsartan (ARNi) rather than ACEi/ARB for NYHA class II-III symptoms 1
• Diuretics should be used as needed for congestion but adjusted according to volume status 1

Implementation Strategy

Timing of Initiation

• In-hospital initiation of GDMT is strongly recommended, as deferring has been associated with patients never receiving therapy 1
• The STRONG-HF trial demonstrated that rapid, high-intensity up-titration of GDMT within 2 weeks of discharge significantly reduced symptoms, improved quality of life, and decreased mortality and HF readmissions at 180 days 1
• This intensive treatment approach reduced the risk of the primary endpoint of mortality or HF hospitalization at 180 days by 34% 1

Medication Sequencing

• Start medications that have the least impact on blood pressure first (SGLT2 inhibitors, low-dose MRAs) 1
• Gradually introduce other drugs through conservative up-titration 1
• The process of increasing dosage might extend over 4-6 weeks, requiring close monitoring and small incremental adjustments 1
• Each drug should be added sequentially with careful monitoring 1

Monitoring Parameters

• Assess blood pressure, heart rate, volume status, and renal function before initiating therapy 1
• Monitor renal function closely, especially when using ACEi/ARB/ARNi and MRAs 2
• Safety indicators to guide up-titration include: eGFR <30 ml/min/1.73 m², serum potassium >5.0 mmol/L, SBP <95 mmHg, HR <55 bpm 1
• Patients with lower baseline blood pressure may require more gradual up-titration and closer monitoring after discharge 1

Special Considerations

Clinical Conditions Requiring Caution

• Low blood pressure can be particularly problematic in patients with significant peripheral vascular disease, bilateral carotid stenosis, recent cerebrovascular events, bowel ischemia, end-stage renal disease on dialysis, and autonomic dysfunction 1
• Avoid medications that may worsen HF, such as diltiazem or verapamil 2
• Avoid the triple combination of ACEi, ARB, and MRA due to increased risk of renal dysfunction and hyperkalemia 2

Optimization Strategies

• Multidisciplinary HF clinics significantly improve GDMT initiation and optimization 3
• Patients seen in HF clinics are more likely to receive appropriate GDMT across all medication classes (HR 1.54-2.49) 3
• Nurse-directed GDMT titration programs successfully increase the number of medications patients can tolerate while enhancing ejection fraction and reducing rehospitalization rates 4

Importance of Comprehensive GDMT

• Increasing the number of medication classes optimized to ≥50% target dose is associated with improved 30-day hospitalization-free survival and 1-year survival (HR 0.74 per extra medication) 5
• Initiation and/or uptitration of beta-blockers and RAS inhibitors during hospitalization is associated with improved 30-day hospitalization-free survival and 1-year survival 5
• Comprehensive therapy with sacubitril/valsartan, beta-blocker, MRA, and SGLT2 inhibitor may further reduce the risk of death and worsening HF compared with standard treatment 1
• Even if all four drugs cannot be introduced, a regimen with a simple GDMT score ≥5 (based on medication combinations and dosages) may lead to improved prognosis in HF patients 6

Common Pitfalls and How to Avoid Them

• Underutilization of evidence-based beta-blockers: Only 63.8% of eligible patients receive appropriate HF beta-blockers despite 92.6% receiving any beta-blocker 3
• Low rates of MRA prescription: Only 17.6% of eligible patients receive MRAs in the first year after diagnosis 3
• Suboptimal dosing: Only 25.3% of patients are discharged on ≥50% target dose of beta-blockers and only 15.6% on ≥50% target dose of RAS inhibitors 5
• Clinical inertia: Traditional step-by-step up-titration of each drug class before starting the next leads to suboptimal implementation 1
• Excessive focus on blood pressure alone: BP is insufficient to guide therapy and predict prognosis; a comprehensive clinical assessment is crucial 1