What are the guidelines for initiating Guideline-Directed Medical Therapy (GDMT) in patients with decompensated heart failure?

Guideline-Directed Medical Therapy Initiation in Decompensated Heart Failure

Start GDMT during hospitalization after hemodynamic stabilization (≥24 hours post-admission), initiating all four medication classes simultaneously at low doses before discharge, followed by rapid uptitration over 6 weeks with frequent monitoring. This intensive strategy reduces mortality and HF hospitalization by 34% compared to usual care. 1

Evidence for In-Hospital Initiation

The STRONG-HF trial definitively demonstrated that simultaneous initiation of multiple GDMT classes before hospital discharge, with rapid uptitration post-discharge, reduces the composite endpoint of mortality or HF hospitalization at 180 days by an absolute 8.1% (number-needed-to-treat of 12). 1 This approach came with no significant increase in serious adverse events despite concerns about safety. 1

• Hospitalized patients are already in a closely monitored environment, which supports the safety of routine in-hospital initiation while improving likelihood of adherence outside the hospital. 1
• Most clinical trials started therapy after a period of stabilization following hospital admission (≥24 hours after admission) and required patients to have hemodynamic stability (no cardiogenic shock, not receiving inotropic therapy, no mechanical support). 1
• Deferring in-hospital initiation of GDMT has been consistently associated with patients never being initiated on therapy, or at best, only after substantial delay. 1

The Four Pillars of GDMT

All patients with HFrEF should receive quadruple therapy consisting of: 1, 2

1. Renin-angiotensin system inhibitors (ARNi preferred over ACEi/ARB)
2. Beta-blockers (bisoprolol, carvedilol, or metoprolol succinate)
3. Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
4. SGLT2 inhibitors (dapagliflozin or empagliflozin)

Specific Initiation Protocol

Starting Doses at Hospital Discharge 2, 3

• Sacubitril/valsartan: 24/26 mg twice daily (lower if not on ACEi/ARB previously)
• Beta-blockers: Carvedilol 3.125 mg twice daily OR Metoprolol succinate 12.5-25 mg once daily
• MRA: Spironolactone 12.5-25 mg once daily OR Eplerenone 25 mg once daily
• SGLT2i: Dapagliflozin 10 mg once daily OR Empagliflozin 10 mg once daily

Post-Discharge Monitoring Schedule

The STRONG-HF protocol requires 4 in-person clinic visits over 6 weeks, though this may not be feasible at all centers. 1 However, multiple early post-discharge visits (whether in-person, pharmacist-led, or virtual) with serial laboratory assessments are essential for maximizing safety and facilitating titration. 1

• Week 1: Check renal function and electrolytes 4
• Week 2: First uptitration if tolerated 2
• Week 4: Check renal function and electrolytes, second uptitration 4, 2
• Week 6: Final assessment and continued titration toward target doses 1

Uptitration Strategy

Titrate medications as frequently as every 1-2 weeks depending on symptoms, vital signs, and laboratory findings to reach target doses. 1, 2 The 2025 European guidelines specifically recommend this intensive strategy of initiation and rapid uptitration before discharge with frequent follow-up in the first 6 weeks (Class I, Level B). 1

Target Doses 3

• Sacubitril/valsartan: 97/103 mg twice daily
• Carvedilol: 25 mg twice daily (or 50 mg twice daily if >85 kg)
• Metoprolol succinate: 200 mg once daily
• Spironolactone: 25-50 mg once daily 4
• Dapagliflozin: 10 mg once daily
• Empagliflozin: 10 mg once daily

Patients should receive at least 50% of target dose for adequate treatment effect. 3 Studies demonstrate a dose-response relationship, with higher doses providing greater benefits than lower doses. 3

Safety Monitoring Parameters

Do NOT uptitrate if: 4, 2

• Serum potassium >5.0 mEq/L (hold MRA if >5.5 mEq/L)
• Worsening renal function (rising creatinine)
• Symptomatic hypotension with postural changes
• Heart rate <50 bpm

Before Reducing GDMT Doses 2

Evaluate for:

• Over-diuresis (most common cause of hypotension)
• Non-cardiovascular drugs with hemodynamic effects
• Autonomic dysfunction

Use best-tolerated doses of GDMT, accepting that lower doses may be necessary, rather than discontinuing therapy entirely. 2

Implementation Support Systems

Virtual care team-guided strategies and pharmacist-led interventions significantly improve GDMT optimization. 1 The Bhatt 2023 trial showed that virtual care team guidance increased GDMT intensifications during hospitalization (50% vs 28%, P=0.001) with no increase in safety events. 1

• Nurse-coordinated HF education with postdischarge telephonic medication titration increases achievement of target beta-blocker doses from 8.5% to 39.1% (P<0.001). 1
• Electronic health record best practice alerts that are prescriptive about specific medication changes increase GDMT class prescription by 41% relative increase. 1

Common Pitfalls to Avoid

Do not wait for outpatient follow-up to initiate GDMT. 1 The subjective location of care (inpatient vs outpatient) should not determine appropriateness for therapy—objective clinical characteristics matter. 1

Do not attribute all adverse events to GDMT. 3 Adverse events are common in HF patients but are often not attributable to GDMT, with rates of adverse events similar between active medication and placebo in clinical trials. 3

Do not discontinue GDMT if ejection fraction improves to >40%. 2 Continue GDMT in patients with HFimpEF (heart failure with improved ejection fraction). 2

Cost-Effectiveness

An intensive GDMT optimization program is extremely cost-effective with incremental cost-effectiveness ratios <$10,000 per quality-adjusted life-year. 5 Optimal quadruple GDMT implementation results in the most gains in life-years. 5